Devices and methods for the delivery and injection of therapeutic and diagnostic agents to a target site within a body

ABSTRACT

The present invention includes systems, devices and methods for delivering and injecting a solution or agent into a target site within the body for the purpose of treating or diagnosing the target site. The target site may be bodily tissue (such as an organ, vessel or bodily lumen), bodily substances (such as a tumor, plaque and thrombus) or synthetic material attached to bodily tissue (such as an artificial graft). The systems and devices of the present invention include injection systems and components for accurately and precisely delivering, injecting and perfusing a therapeutic or diagnostic agent, preferably in a fluid form, directly into the target site without the need to penetrate the tissue with anything other than the agent itself. More specifically, none of the embodiments employ a needle or other penetrating device for creating a space within which the agent is injected. The injection systems include embodiments for use in intraoperative and interventional clinical settings, and generally comprise, at least in part, a propulsion apparatus, a reservoir, often called a syringe or ampule, for receiving and holding the solution or agent, and a dispersion means for transporting the solution or agent from the reservoir to the target site and for perfusing or dispersing it within the target site. The surgical and endovascular methods of the present invention include methods for injecting an agent into a target site within the body for the purpose of treating and/or diagnosing a target site or tissue adjacent a target site. Various therapeutic applications in which the invention may be employed include but are not limited to the treatment of cardiac, cardiovascular, peripheral vascular, and neurovascular diseases, AV access graft stenosis and thrombus formation, cancer, rheumatoid arthritis, etc. More specific examples of the types of applications that can be accomplished by the present invention include, for example, the administration of angiogenic solutions to an ischemic area of myocardium, the delivery of a thrombolytic drug to a thrombus within a chamber of the heart or to the peripheral or neuro vasculature, administration of a solution to a portion of the atria contributing to atrial fibrillation, or the delivery of an anti-angiogenic solution to a solid tumor or through the vasculature supplying blood to a malignancy.

FIELD OF THE INVENTION

[0001] This invention includes various medical devices and systems foruse in surgical and interventional procedures. More particularly, theinvention relates to devices and systems for the delivery and injectionof therapeutic and diagnostic agents, solutions or injectates intobodily tissue, bodily substances or synthetic materials attached tobodily tissue, such as an artificial graft. Additionally, the inventionrelates to methods of delivering and injecting a solution at a targetsite within the body for the treatment or diagnosis of that target site.

BACKGROUND OF THE INVENTION

[0002] Despite the continual advances in medical technology,particularly in the treatment of heart disease, vascular disease,cancer, pain, allergies, orthopedic repair and many other diseases andconditions, there are a significant number of patients for whomconventional surgical and interventional therapies are not feasible orare insufficient to treat the disease or condition. For many patients,medical treatment with drugs and the like is the only feasible treatmentavailable.

[0003] There have been many recent advances in drug therapies,particularly with regard to cell or site-specific therapeutics (asopposed to systemic therapeutics) such as pharmacologic agents (e.g.,anesthetics and analgesics) and biologic agents (e.g., geneticallyengineered material). Unlike the systemic administration oftherapeutics, typically taken orally or given intravenously, much of theeffectiveness of cell- or site-specific therapeutics is based on theability to accurately and precisely deliver the therapeutics to thetargeted site within the body.

[0004] Needle injection devices are the most commonly used means for thesite-specific administration of agents or solutions. Although there havebeen advances in needle-based drug delivery injection systems, thesesystems have significant shortcomings and disadvantages. Theseshortcomings and disadvantages are exemplified, for example, in genetherapy applications—the implantation of genetic material or engineeredcells in specific targets in the human anatomy to create a therapeuticor preventative effect.

[0005] Depending on the disease being treated, gene therapy can beangiogenic or anti-angiogenic. The intended result of angiogenic therapyis the promotion of angiogensis—a complex biological process thatresults in the growth of new blood vessels. Angiogenic therapy has beenused experimentally for treating, for example, cardiac ischemia,coronary artery disease (e.g., atherosclerosis), and ischemia inperipheral vascular beds. Conversely, anti-angiogenic therapy involvesthe reduction in the proliferation of blood vessels, for example, tocut-off the supply of blood to a tumor or to proliferating pannus-typetissue, and to inhibit the abnormal growth of retinal vessels that leadsto blindness.

[0006] An important factor in achieving the desired result of genetherapy is direct exposure of the genetic material to a specific targetsite for a sustained period of time. This is particularly challengingfor gene therapies that require delivering genetic material to thenuclei of cells. Depending on the location of the targeted tissue andthe type of condition being treated, exposure of the genetic material tothe target site may involve direct approaches, such as an open or lessinvasive surgical approach, or endovascular approaches by means of acatheter. With any approach, there are significant challenges in thedelivery of genetic material to the appropriate cells of the patient ina way that is specifically targeted, efficient and safe.

[0007] For optimum “up regulation” of the gene therapy agent, the agentmust undergo some atomization in order to be effectively perfused withinthe target site. If the gene therapy drug is not sufficiently atomized(i.e., broken up into very small micro-particles), dispersion and thenabsorption of the drug may be greatly reduced, resulting in minimal tono positive affect on the patient. Needle-based syringes are not capableof such atomization and, instead, deliver the injectate in the form of abolus, which is less likely to be effectively dispersed and absorbedwithin tissue.

[0008] Moreover, in certain applications of gene therapy, it isimportant to minimize the systemic exposure of the gene therapy agent inorder to avoid unwanted side-affects. The use of a needle or otherpenetrating means to inject the targeted tissue area unavoidablyinvolves making a hole into the target site. This results in much of theinjectate leaking back out of the hole, and being released systemicallythroughout the body or being wasted. This also results in increasedtreatment costs and requires more injections, time and agent to achievethe desired affect.

[0009] Gene therapy has been used, for example, to create angiogenesisin hypoxic (i.e., oxygen-deprived) heart tissue. In a cardiac surgicalprocedure, the angiogenic solution is typically delivered by making anumber of syringe injections, typically in a grid-like pattern, directlythrough the epicardium (i.e., the outer surface of the heart) at theischemic portion of the myocardium. An equivalent endocardial approach(i.e., through the inside surface of the heart) involves delivering acatheter employing a distal needle to within a ventricular chamber andinjecting the angiogenic solution through the endocardium to themyocardium. The intent of both approaches is to cause the cells in thetarget tissue to express the desired growth factor protein continuouslyfor a desired time period. Other means of delivering cardiacangiogenesis agents include injecting the agent within the pericardialsac (i.e., intrapericardial), within the coronary arteries (i.e.,intracoronary) or directly into the myocardium (i.e., the middle layerof the heart wall).

[0010] Although some recent clinical studies have suggested that thereis some marginal resulting angiogenic response with syringe/needle-basedinjection, there are definite disadvantages of employing asyringe/needle-based injector or other tissue-penetrating device. Forexample, myocardial ischemia typically involves an affected surface areain the range of approximately 3 mm² to 10 mm². A single needle injectionin ischemic tissue can only provide a solution dispersion in a muchsmaller area defined by the size of the needle and the limited abilityof the agent to diffuse through the tissue. Thus, multiple needle-basedinjections may be required in order to sufficiently disperse thesolution over the entire affected area. As the number of injectionsincreases, the procedure time is increased and a greater volume of thegene therapy agent is required to effectively treat the ischemic area.More time and greater drug volume increase the cost of the procedure.

[0011] Furthermore, it is known that needle injections or penetrationinto the tissue can traumatize or destroy tissue cells and, as a result,increase a patient's risk of post-operative arrhythmia. This isparticularly due to the difficulty in precisely controlling thepenetration of the needle during injection. The more injections orpenetrations, the greater the cell destruction and risk of arrhythmia.Still another disadvantage of multiple needle-based injections of growthfactor is the need to carefully track the location of each injectionsite so as to prevent the accidental delivery of growth factor tonon-diseased tissue.

[0012] There are some gene therapies that do not involve needle-baseddrug delivery. Instead, indwelling catheters and drug-infused stentshave been used for releasing the therapeutic agent in a steady,controlled-release fashion. These approaches present a greater risk ofreleasing the agent systemically. Additionally, it is more difficult toassess the actual dosing of the target area that takes place. Thus,these approaches have the disadvantages of being less effective, not assafe, and more costly than injections.

[0013] Another condition in which site-specific or local drug deliveryis commonly employed is in the treatment of peripheral vascular disease(such as deep vein thrombosis and embolisms). One such treatment isvenous lytic therapy, the dissolving of blood clots (thrombus) in theperipheral vasculature (e.g., femoral and illiac arteries and veins).Lytic therapy involves systemically infusing thrombolytics, such asurokinase, streptokinase, reteplase and tPA. Other more recentlydeveloped procedures involve directly delivering the thrombolytics intothe thrombus site through the use of indwelling infusion catheters. Inorder to effectively lyse the thrombus, the thrombolytics are typicallyinfused for many hours, even as much as a day or more, increasing thenecessary length of hospital stay and the overall cost of the procedure.

[0014] Still another area in which the localized delivery oftherapeutics is indispensable is in the treatment of arterial-venous(AV) access routes for renal dialysis. There are several ways in whichAV access is established. One is by means of an AV graft, a tube made ofa synthetic material such as teflon (e.g., PTFE), which is implanted toconnect an artery and vein in the arm, for example. The graft takesapproximately two weeks to mature and should be placed at least a fewweeks before use for hemodialysis. Unfortunately, these grafts are proneto stenosis and the spreading of infection, and typically only survivefor not more than about 1½ years. Another type of AV access route is anAV fistula. This is a surgical connection made between an artery and avein. The fistula, once surgically placed, takes around twelve weeks tomature, and thus must be placed several months before hemodialysis isanticipated. Although the infection and stenosis rate of fistulas is farless than that of AV grafts, infection and stenosis are not uncommon.

[0015] Double lumen catheters are another type of AV access means. Themay be used for long-term or temporary applications. Those used longterm are surgically placed in a tunneling fashion under the skin. AVaccess catheters are typically placed into either the subclavian orjugular vein. Occasionally, they are temporarily placed in the femoralvein. Short-term AV access catheters are generally placed when dialysisis needed emergently either when the referral of the patient to dialysisis unduly delayed, or when a permanent AV access fails and the patientis too unstable to have it revised until after an emergency treatment.AV access catheters may develop serious infections, or may thrombose,ultimately leading to failure of the device. Moreover, the veins theyare placed in-are prone to clotting.

[0016] Conventional treatments for problems (e.g., stenosis, infectionand thrombus formation) that may arise with AV access grafts, fistulasor catheters typically involve surgical intervention, including therepair or replacement of the AV access device, the physical removal ofstenotic plaque and the chemical or physical removal of blood clots.Clearly the elimination of any surgical procedure is advantageous toreducing morbidity and pain. Thus, there is still a need for an improvedmeans and method for treating and preventing conditions related to theuse of AV access devices.

[0017] The disadvantages of conventional drug delivery systems alsoexist in the treatment of other conditions such neurovascular disease,cancer, rheumatoid arthritis, etc. Accordingly, there is a need fordevices and methodologies for delivering drugs and other solutions tobodily tissue which are more precise, efficient, and effective, and lesscostly than conventional devices and methods. Additionally, it is highlydesirable to have devices and methods for delivering solutions to bodilytissue that are safer and less invasive than current devices andmethods. There is also a need for medical agent delivery devices thatare packaged and supplied in ways that make their use convenient andeasy for self-application and institutional use. Thus, there stillexists a need for enabling technology for the more effective and safelocal delivery of therapeutic agents.

SUMMARY OF THE INVENTION

[0018] The present invention includes novel means and methods fordelivering and injecting a solution or agent into a target site withinthe body for the purpose of treating or diagnosing the target site. Thetarget site may be an area of tissue or a substance affixed or adjacentto the tissue area or its cells. More specifically, the target site maybe an organ, a body lumen, a vessel lumen, a solid tumor, a syntheticgraft, plaque, thrombus, etc.

[0019] The devices of the present invention include injection systemsand components for accurately and precisely delivering, injecting andperfusing a therapeutic or diagnostic agent, preferably in a fluid form,directly into the target site without the need to penetrate the tissuewith anything other than the agent itself More specifically, none of theembodiments employ a needle or other penetrating device for creating aspace within which the agent is injected.

[0020] The injection systems of the present invention includeembodiments for use in intraoperative and interventional clinicalsettings as well as in certain non-clinical settings in which thepatient injects himself or herself. More specifically, they areconfigured for delivering a solution from an ampule and injecting itinto a target site within the body or within an artificial graft affixedto the body through either a surgical opening, a less invasive surgicalopening (such as through a trocar port), or endovascularly.

[0021] Generally, the injection systems comprise, at least in part, apropulsion apparatus, an ampule reservoir, often called a syringe orampule, for receiving and holding the solution or agent, and adispersion means distal to the ampule for transporting the solution oragent from the reservoir to the target site and for perfusing ordispersing it within the target site.

[0022] The propulsion devices of the present invention produce pressuresgreat enough to inject a solution or agent within the target sitewithout the need for a needle or any other penetrating device. Thesedevices may be powered by any appropriate propulsion mechanism orenergy, such as a spring-loaded member or a self-contained inert gas(such as a cartridge containing carbon dioxide, nitrogen, argon, etc.)for ejecting or propelling an agent out of a reservoir. The propulsionapparatus is operatively coupled to the reservoir and is used to propelthe agent out of the reservoir at a desired pressure such as in therange from about 1800 psi to about 2300 psi. The propulsion devices ofthe present invention further comprises means for selecting the volumeof agent to be propelled from the reservoir as well as means forselecting a pressure at which the agent is propelled from the reservoir.Preferably, the propulsion devices are ergonomically configured to beheld and actuated by one hand of the user.

[0023] The ampule reservoirs of the present invention are intended tohold at least one dose, but may, however, have any appropriate volumefor containing any appropriate dose of solution. The ampule may bereusable or disposable after a single use. The ampule sits within thehousing of the propulsion device with its distal end in sealedengagement with the dispersion means and its proximal end in operativeengagement with a piston which forces the agent out of the reservoirupon activation of the propulsion device. Alternately, the ampule may bemodular form which can be releasably coupled to the dispersion means toform a nozzle assembly which is attachable to the propulsion device. Theampule may come pre-filled from the supplier or may refillable by thephysician.

[0024] The ampule reservoir and dispersions means of the presentinvention each have at least one orifice through which the agent canpass through as it is propelled. The dispersion orifice(s) mostpreferably has a diameter in the range from about 0.1 mm to about 0.3mm. The dispersion means is comprised of material(s) that are capable ofwithstanding the forces of the pressurized fluid to the extent that thepressure of the agent is substantially maintained as it passes throughthe dispersion means.

[0025] The most significant difference between the injection devices foruse in surgical applications and those for use in interventionalapplications is their respective configurations of the dispersion means.In the surgical devices, the dispersion fixture is in the form of afixture attached distally to the ampule reservoir. In the endovasculardevices, it is in the form of a catheter assembly attached distally tothe ampule reservoir. It follows that the means by which the respectivedispersion means attach to the ampule reservoir are also different.

[0026] The various dispersion fixtures for use with the surgicaldevices, for both direct surgical and less-invasive surgical approaches,have an atraumatic surface which, when operatively positioned, faces thetarget site. The one or more dispersion orifices are located in thistarget-facing surface, which, for most of the surgical embodiments ofthe present invention, is smooth and substantially planar. Thetarget-facing surface has a selected shape, size, and number andarrangement of dispersion orifices for defining a selected pattern ofdispersion at the target site. The target-facing surface and/or theorifice arrangement may have a shape or configuration, for example, inthe form of a circle, oval, ellipse, linear array, an annular array oran arched cone. In some less-invasive procedures, the dispersion meanshas a lower profile sufficient to be delivered through a less invasiveopening. For some less-invasive devices of the present invention, thetarget-facing surface is not necessarily planar, but be a rounded,tapered or flat tip of a cannula.

[0027] To enhance the precision and accuracy of dispersion of the agentthrough the dispersion orifices, a jewel having an orifice may becoaxially aligned on the proximal side of each dispersion orifice. Thejewel is made of a very hard material such as stainless steel or aprecious stone such as sapphire. The dispersion orifice(s) are in fluidcommunication with the reservoir orifice(s) by means of one or morepathways situated between them. In the surgical embodiments and someless-invasive embodiments of the present invention, each pathway isdefined by a channel formed either within the dispersion fixture orwithin the distal end of the ampule. In other less-invasive embodiments,the pathway is the lumen of a tube, such as a cannula or other tubularpiece. The tube may be malleable and steerable to facilitate deliverythrough a narrow, sometimes tortuous path to the target site.Additionally, these less-invasive embodiments may further comprise anendoscope.

[0028] The injection devices for use in interoperative or endovascularprocedures employ a catheter as the means for dispersing the injectateinto the target site. The catheters of the present invention are made ofmaterial(s) having physical properties sufficient to maintain thepressure of the injectate as it travels from the reservoir to thedispersion orifice. They each have a proximal end, a distal end having adistal tip, and a lumen there between. The distal tip has at least onedispersion orifice. The proximal end of the catheter is in sealedengagement with a distally tapering reservoir nozzle terminating in areservoir orifice. The engagement is accomplished by means of a couplermechanism, such as a leur fitting. A retainer means is then seated overthe ampule reservoir to further ensure that the coupler mechanism issecurely affixed to the ampule. Collectively, these components provide asealed, fluid pathway from the reservoir to the catheter, and ensure theintegrity of the pathway under pressurized conditions.

[0029] The preferred location of the catheter dispersion orifice(s)varies from embodiment to embodiment, depending on the intraoperativeapplication at hand. Generally, the dispersion orifice(s) are located onthe sidewall of the distal tip or at the distally facing end of the tip.Catheters having the dispersion orifice(s) within the sidewalls ejectthe agent laterally of the catheter tip and define an injection vectorpath that is substantially transverse or perpendicular to thelongitudinal axis of the catheter. The dispersion orifices may bearranged in a circumferential pattern, a helical array, a number oflinear arrays running parallel to the longitudinal axis of the catheter,or any other pattern that is suitable for the application. Cathetershaving the dispersion orifice(s) within the distally facing end of thecatheter tip eject the agent distally of the catheter tip and define aninjection vector path that is substantially coaxial or parallel to thelongitudinal axis of the catheter.

[0030] The present invention further includes various surgical, lessinvasive surgical and endovascular methods for delivering and injectinga solution or agent to a target site within the body or within a graftaffixed to the body without the need to penetrate the target site withother than the solution or agent itself. The present invention alsoincludes methods for treating or diagnosing a target site within thebody by means of a precisely delivered solution or agent. These methodsmay be standalone procedures or may be employed in the context of or asan adjunct to other intraoperative or interventional procedures andtherapies. For example, a method of injecting a therapeutic agent intothe heart may be performed in conjunction with a CABG surgery or acatheter-based, stent placement procedure.

[0031] The surgical and endovascular methods of the present inventioninclude methods for injecting an agent into a target site within thebody for the purpose of treating and/or diagnosing a target site ortissue adjacent a target site. Generally, these methods first involveaccessing the target site within the body. The access site can be eithera direct surgical opening, a less-invasive opening through which a portis placed, or a percutaneous opening through which a catheter isdelivered. An ampule having a reservoir containing a volume of thetherapeutic or diagnostic agent is provided. The volume of agent is thenpropelled from the reservoir at a selected pressure to a locationproximate the target site. This involves exerting a force on the agentcontained within the reservoir to provide the selected pressure. Theselected pressure has a value such that the pressure of the agent as itmakes contact with and disperses within the target site is sufficient tocause the agent to disperse within the target site without penetratingthe target site with any other means. The agent is then dispersed intothe target site in a substantially predefined pattern. When using adisposable ampule with a prefilled volume of agent, the ampule may bereplaced with a second ampule containing a volume of the same or adifferent agent, and then repeating the remaining steps with the secondampule and any additional ampules necessary to complete the procedure.

[0032] As the physician deems appropriate, the step of positioning mayinvolve either contacting a surface of the target site with the endeffector or bringing it to within a selected distance from a surface ofthe target site. In the context of a surgical procedure, an end effectoror dispersion means is-delivered through the surgical opening andpositioned proximate the target site. In a less-invasive surgicalprocedure, this involves delivering the end effector through a smalleropening such as a one made by a trocar port and steering the endeffector towards the target tissue area. The less-invasive method mayalso involve the use of an endoscope to view some of the steps of theprocedure. Similarly, in an endovascular procedure, a catheter isinserted into a percutaneous opening and the catheter tip is deliveredproximate to the target site. The percutaneous opening may also be theexternal opening of an AV access graft.

[0033] The present invention also includes methods of diagnosing atarget site. These methods generally involve percutaneously accessingthe vasculature of a patient. A catheter having a non-penetratingcatheter tip is provided and placed in fluid communication an ampulereservoir containing a volume of a diagnostic agent. The catheter isthen inserted into the percutaneous access site, and its non-penetratingtip is then delivered proximate to the target site. A volume of thediagnostic injectate is then injected through the catheter and into thetarget site in a substantially predefined dispersion pattern at apressure sufficient to cause the agent to disperse within the targetsite. The dispersion occurs without penetrating the target site with thecatheter. Finally, the area proximate the target site is then viewedunder fluoroscopy in order to determine the optimal location and tissuedepth for injecting a therapeutic agent.

[0034] The invention is useful in the delivery and injection of precise,predetermined volumes of a therapeutic agents or solution directly to atarget tissue site most commonly through a parenteral route. The morecommon parenteral routes and target sites are identified below in thefollowing chart as well as agents commonly administered via theseroutes. It should be noted that this chart is intended to beillustrative only, and not intended to be a complete, comprehensivelisting. Route/Target Site Commonly Administered Agents IntravenousAntibiotics, anti-inflammatory agents, analgesics, (Within vessel)antineoplastics, vasoactive agents, electrolyte solutions,corticosteroid solutions, thrombolytics, anticoagulants, anticoagulantantagonists, antiarrythmics, beta blockers, vasodilators, etc.Intra-arterial Antineoplastic agents, antithrombolytics, gene therapyagents (Arteries; commonly (clinical testing) the coronary arteries)Intra-articular Corticosteroid suspensions (Joint: ankle, elbow, knee,shoulder, hip, digits) Intracardiac (Heart: Vasoconstricors, calcium,gene therapy agents (clinical myocardium, ventricle, testing),antibiotics pericardial sac) Intradermal Antibiotics, tuberculin,allergens (Dermal layer of skin: forearm, back, scapula) Intraspinal orepidural Anesthetics, analgesics (Spinal column) IntrathecalAnesthetics, analgesics (Spinal fluid) Intramuscular Sedatives,vitamins, vaccines, narcotics, antitoxins (Muscle: deltoid, gluteousmedius, gluteous minimus) Subcutaneous Insulin, narcotics, vaccines,vitamins (Beneath the skin)

[0035] Various therapeutic applications in which the invention may beemployed include but are not limited to the treatment of cardiac,cardiovascular, peripheral vascular, and neurovascular diseases, AVaccess graft stenosis and thrombus formation, cancer, rheumatoidarthritis, etc. More specific examples of the types of applications thatcan be accomplished by the present invention include, for example, theadministration of angiogenic solutions to an ischemic area ofmyocardium, the delivery of a thrombolytic drug to a thrombus within achamber of the heart or to the peripheral or neuro vasculature,administration of a solution to a portion of the atria contributing toatrial fibrillation, or the delivery of an anti-angiogenic solution to asolid tumor or through the vasculature supplying blood to a malignancy.Although only a few specific examples of target sites, delivery routesand therapeutic and diagnostic agents are specifically discussed here,any target site, any appropriate delivery route to a target site and anytype of injectate may be delivered by the present invention. Theinjectates can include all classes of drugs, such as biological agents,pharmaceuticals and biopharmaceuticals, as well as solutions, such assaline and ethanol, which are not considered to be drugs. In addition tothe primary function of delivering and dispersing the injectate, thecatheters of the present invention may also perform adjunct functions,such as dilation of a vessel by means of an expandable member such as aballoon.

DESCRIPTION OF THE DRAWINGS

[0036]FIG. 1A is a schematic representation of an embodiment of a priorart injection system having an externally attached syringe or ampule.

[0037]FIG. 1B is a schematic representation of an embodiment of a priorart injection system having an internally housed syringe or ampule.

[0038]FIG. 2A is a perspective view of one embodiment of a nozzleassembly for coupling to a delivery injection system of the presentinvention for use in a direct surgical application.

[0039]FIG. 2B is a lengthwise cross-sectional view of one configurationof a nozzle body of the present invention.

[0040]FIG. 2C is a perspective view of the nozzle body of FIG. 2Bwherein channels located on the distal end of the nozzle body facilitatedelivery of an injected solution from an ampule reservoir to dispersionorifices

[0041]FIG. 3 shows a scaled view of the distal end configuration of aninjection device of the present invention.

[0042]FIG. 4A is a view of the distal end of one embodiment of adispersion fixture of the present invention having a plurality ofdispersion orifices.

[0043]FIG. 4B is an underside view of the dispersion fixture of FIG. 4Aillustrating the location and configuration of channels which facilitatedelivery of an injected solution from an ampule reservoir to dispersionorifices.

[0044]FIG. 4C is a cross-sectional side view of the dispersion fixtureof FIGS. 4A and 4B.

[0045]FIG. 4D is a magnified view of the cut-away portion of FIG. 4Cdefined by circular line D, illustrating the details of theconfiguration of a particular embodiment of a dispersion orifice havinga jewel operatively positioned within it.

[0046]FIG. 4E is a magnified cut-away view similar to that of FIG. 4C,illustrating another embodiment of a dispersion orifice suitable for usewith the present invention.

[0047]FIG. 5 is a magnified cross-sectional view of the nozzle body ofFIG. 2A operatively coupled with another embodiment of a dispersionfixture of the present invention.

[0048]FIG. 6A is a view of the underside of another embodiment of adispersion fixture of the present invention having circular shape and aplurality of dispersion orifices symmetrically aligned along theperimeter of the fixture and being equidistant from the focal point ofthe fixture.

[0049]FIG. 6B is a view of the underside of another embodiment of adispersion fixture of the present invention also having circular shapeand a plurality of dispersion orifices but with the orifices havingvarying distances from the focal point of the fixture.

[0050]FIG. 6C is a view of the underside of another embodiment of adispersion fixture of the present invention having an oval shape and aplurality of dispersion orifices with varying distances from the focalpoint of the fixture.

[0051]FIG. 6D is a view of the underside of yet another exemplaryembodiment of a dispersion fixture of the present invention having theshape of a baseball diamond. The plurality of dispersion orifices areequidistant from the focal point and are aligned along the perimeter butonly along the length of the arched side.

[0052]FIG. 7A is a cross-sectional front view of another embodiment ofthe present invention having a dispersion fixture that provides asolution flow path transverse to the tissue surface being targeted. Thisembodiment also features malleable tubing connecting the dispersionfixture to the ampule to provide for more flexibility and range ofmotion.

[0053]FIG. 7B is a magnified bottom view of the dispersion fixture ofFIG. 7A.

[0054]FIG. 7C is a view of the jewel plate of the dispersion fixture ofFIG. 7B.

[0055]FIG. 7D is a cross-sectional side view of the jewel plate of FIG.7C.

[0056]FIG. 7E is a top view of an alternate embodiment of a jewel platefor use with the present invention.

[0057]FIG. 8A is a perspective view illustrating an embodiment of asolution injection system of the present invention in use in a cardiacsurgical procedure.

[0058]FIG. 8B illustrates use of an embodiment of a solution injectionsystem of the present invention operatively positioned on the epicardiumto treat an ischemic portion of the myocardium (shown in cross-section)affected by a subendocardial infarct.

[0059]FIG. 8C is a cross-sectional view illustrating use of thedispersion fixture of FIG. 6A operatively positioned on the epicardiumto treat an ischemic portion of the myocardium affected by a transmuralinfarct.

[0060]FIG. 8D is a cross-sectional top view of another embodiment of asolution injection system of the present invention employing thedispersion fixture of FIG. 6D operatively positioned on the epicardiumto treat a ischemic portion of the myocardium affected by a transmuralinfarct

[0061]FIG. 9 is a perspective view illustrating an embodiment of asolution injection system of the present invention in use in a lessinvasive cardiac surgical procedure.

[0062]FIG. 10 is a perspective view illustrating another embodiment of asolution injection system of the present invention in use in a lessinvasive cardiac surgical procedure.

[0063]FIG. 11A is a longitudinal view of the general configuration of acatheter dispersion means and ampule nozzle assembly for an embodimentof a solution dispersion means for use in endovascular applications.

[0064]FIG. 11B is a cross-sectional view along the length of the nozzleassembly of FIG. 11A.

[0065]FIG. 11C is a perspective view of the coupler of FIG. 11B.

[0066]FIG. 11D is a cross-sectional view along the length of the couplerof FIG. 11C.

[0067]FIG. 11E is a magnified cross-sectional view of the hypotube tipof the coupler of FIGS. 11C-D.

[0068]FIG. 11F is a perspective view of an embodiment of a retainer foruse with the dispersion means of FIG. 11A.

[0069]FIG. 11G is a perspective view of another embodiment of a retainerfor use with catheter-based solution dispersion means of the presentinvention.

[0070]FIG. 12 is a side view of one embodiment of a side-shootingcatheter tip for use with catheter-based solution dispersion means ofthe present invention.

[0071]FIG. 13A is a top view of a portion of cardiac vasculature inwhich another embodiment of a side-shooting catheter tip is shown in usein a transvascular application.

[0072]FIG. 13B is a cross-sectional view of FIG. 13A taken transverse tothe longitudinal axis of the catheter and vessels.

[0073]FIG. 14A is a top view of a portion of a coronary artery affectedby atherosclerotic stenosis having another embodiment of a side-shootingcatheter tip of the present invention operatively positioned proximallyof the stenotic region.

[0074]FIG. 14B is a top view of a portion of a coronary artery affectedby atherosclerotic stenosis having the catheter tip of FIG. 14Aoperatively positioned distally of the stenotic region.

[0075]FIG. 15 is a top view of a portion of a coronary artery affectedby atherosclerotic stenosis having another embodiment of a side-shootingcatheter tip comprising angioplasty capabilities, and which isoperatively positioned at a stenotic region.

[0076]FIG. 16A is a perspective view of an embodiment of an end-shootingcatheter tip for use with a catheter-based solution dispersion means ofthe present invention.

[0077]FIG. 16B is a longitudinal cross-sectional view of the cathetertip of FIG. 16A.

[0078]FIG. 16C is a longitudinal cross-sectional view of the cathetertip of FIG. 16A operatively positioned in the end of a catheter for usewith a solution dispersion means of the present invention.

[0079]FIG. 17 illustrates an end-shooting catheter-based dispersionmeans of the present invention in use in an intra-chamber applicationfor delivering a solution to the endocardium.

[0080]FIG. 18A illustrates a multi-orifice embodiment of amulti-orifice, end-shooting catheter-based dispersion means of thepresent invention in use in an intravascular application for deliveringa solution to within a peripheral vessel.

[0081]FIG. 18B is a magnified cut-out view of the catheter tip of thedispersion means of FIG. 18A ejecting a solution to treat a thrombus.

[0082]FIG. 19A is a cross-sectional view of a medial portion of a humanbrain wherein a multi-orifice, end-shooting catheter-based dispersionmeans has been to delivered to a site within the neurovasculature.

[0083]FIG. 19B is a magnified cut-out view of the catheter tip of thedispersion means of FIG. 19A ejecting a solution to treat a thrombus.

DETAILED DESCRIPTION OF THE INVENTION

[0084] With reference to the accompanying drawings (wherein like numbersreference like elements), certain preferred embodiments of the devicesand methods of the present invention will now be described in greaterdetail.

[0085] As mentioned above, the present invention includes injectionsystems and methods for injecting and delivering an agent or solution toa target site in the body for the treatment or diagnosis of that targetsite. The injection systems comprise, at least in part, a propulsiondevice, a reservoir, often called a syringe or ampule, for receiving andholding the agent or solution, and dispersion means for transferring theagent or solution from the reservoir to the target site.

[0086] The propulsion device of the present invention may have aconfiguration similar to current needle-free injection devices, commonlyreferred to as jet injectors. Some of these devices include those madeby National Medical Products, Inc., BioJect, Inc., Medi-Ject, Inc.,Weston Medical Ltd. Visionary, Medical Products Corp. and EquidyneSystems, Inc. that are primarily designed for hypodermic applications,such as for the delivery of insulin for the treatment of diabetes.PowderJect Pharmaceuticals PLC is another manufacturer specializing inthe needle-free injection of atomized solid materials. These injectiondevices are capable of injection in the range from about 2000 to about4500 psi. Examples of such injection devices are disclosed in U.S. Pat.Nos. 5,383,851, 5,399,1635,520,639, 5,730,723, 5,746,714, and 5,782,802,which are hereby incorporated by reference.

[0087]FIGS. 1A and 1B are schematic drawings of exemplary prior artinjection or propulsion devices which, with certain modifications, canbe used with the present invention as a propulsion device. In FIG. 1A,propulsion device 10 has a syringe or ampule 18 attached to the distalend 12 of injection device 10. Ampule 18 may be reusable (refillable) ormay be disposable and replaceable with other sterilized ampules. FIG. 1Billustrates another embodiment of a propulsion device 20 of the presentinvention which has an ampule 28 (shown in phantom) housed within thedistal end 22 of injection device 20. With this internal ampule design,an entirely disposable injection device is feasible. The ampules of bothembodiments may be supplied pre-filled with a selected volume of theinjectable solution.

[0088] Propulsion devices 10, 20 each include a housing 14, 24,respectively, which is preferably made of biocompatible plastic, andpreferably have a general shape, size and weight so as to readily fit ina users hand. Housing 14, 24 houses a propulsion mechanism (not shown),typically either a spring-loaded mechanism or self-contained volume ofgas, such as carbon dioxide, helium, argon or nitrogen. The gas iscontained within a sealed cartridge that may be interchangeable withother cartridges. Other propulsion mechanisms, such as those driven byelectromechanical or hydrolic power may also be used with the presentinvention. When triggered, the propulsion mechanism releases itspotential force to supply an appropriate amount of pressure or force tothe proximal end of a piston (also not shown). The distal end of thepiston is typically positioned within the proximal end of an ampule andimpinges on the volume of solution within the ampule reservoir causingits contents to be forced out the reservoir.

[0089] The propulsion devices of the present invention may employ anyappropriate propulsion mechanism capable of providing a force having apressure preferably in the range from about 1800 psi to about 5000 psi.With respect to some of the specific applications discussed below,acceptable pressures may be in the range from about 1800 psi to about2300 psi. It should be noted, that the most appropriate pressure for agiven application will primarily be dictated by the viscosity of theinjectate, the desired depth of penetration, and the type and thicknessof the tissue or substance being injected, i.e., muscular tissue,vascular tissue (e.g., cardiovascular, peripheral and neuro), collagen,ocular tissue, cartilage, a tumor, fibrous substances (e.g., thrombus),blood-borne substances (e.g., plaque), etc. Too low of an injectionpressure will result in a lack of penetration and dispersion of theinjectate while too great of an injection pressure may result in traumato the tissue site, possibly to the point of puncturing or rupturing thetissue, and overshooting the injectate beyond the desired penetrationdepth.

[0090] Those skilled in the art will appreciate that the factorsaffecting pressure (e.g., solution viscosity, desired depth of solutionpenetration, and tissue type and thickness) will in turn dictate certaindesign specifications of the injection devices, which will necessarilyneed to be implemented in order to achieve the desired injectionpressure for a given application. These design specifications includebut are not limited to the size of the dispersion orifice(s) and thecolumnar and wall strengths of the dispersion means. With respect tosome of the specific applications discussed below, acceptable dispersionorifice diameters are preferably be in the range from about 0.1 mm toabout 0.3 mm.

[0091] The propulsion mechanism of propulsion devices 10, 20 isactivated by means of a trigger mechanism 16, 26, respectively,ergonomically located for activation by a users finger. When activated,the propulsion mechanism supplies the requisite force or pressure toampule 18, 28, respectively, causing the solution within to be propelledfrom injection device 10, 20 through a dispersion means or mechanism(not shown) which in turn channels the solution to the targeted site.The propulsion devices of the present invention may comprise componentsthat allow the user, prior to activation of the propulsion mechanism, toselect the desired volume of solution to be delivered to the target siteand or the desired pressure at which the solution is propelled from thereservoir.

[0092] The dispersion means of the present invention is the component ofthe injection system that directs the agent or solution from within thesyringe or ampule to the target site. Such dispersion means is definedby the configuration of an end effector assembled or affixed to thedistal end of the propulsion device or ampule reservoir of the injectionsystem. The specific configuration of the end effector primarily dependson the approach being used to access the targeted tissue site within thebody. The various approaches include a direct surgical approach (orsurgery), a less invasive surgical approach through a small incision orport, or an endovascular approach (sometimes referred to as acatheter-based approach). The end effector for use in a direct orless-invasive surgical approach is more likely to be in the form of afixture having openings for dispersing the injectate. Depending on thesize of the access space and the level of difficulty in reaching atarget site in a less-invasive surgical approach, the fixture may have avery low profile fixture and an may incorporate means for facilitatingdelivery through a tortuous and lengthy access space. On the other hand,the end effector for use in an endovascular approach is in the form of acatheter. Regardless of the approach used, none of the end effectors ofthe present invention is designed or intended to penetrate or pierce thetarget site directly. Instead, only the agent or solution being injectedby the present invention is intended to penetrate the target site withminimal trauma to tissue or adjacent substances. In fact, in some casesit may be preferable to avoid directly contacting the target site withthe end effector. The injection systems of the present invention arecapable of achieving the desired delivery and dispersion of an injectateto the target site without directly contacting the tissue, if sodesired.

[0093] As mentioned above, the dispersion means of the present inventionfor use in a direct surgical approach for accessing a target site on theouter surface of an organ or bodily tissue includes a non-penetratingend effector or fixture, such as a cap, mounted to or integral with thedistal end of the propulsion device (such as with injection system 20 ofFIG. 1B). Alternatively, the dispersion means may be assembled with anampule in a nozzle configuration, which in turn is functionally coupledto the distal end of the propulsion device (such as with injectionsystem 10 of FIG. 1A).

[0094]FIG. 2A is a perspective view of an embodiment of an end effectorintegral with a nozzle assembly 30 for attachment to a propulsion devicesuch as that of FIG. 1A. Nozzle assembly 30 includes an ampule body 32and end effector 40. Ampule body 32 has a generally cylindricalconfiguration, and preferably has a length in the range from about 3 cmto about 4 cm and an outer diameter in the range from about 1.2 cm toabout 1.5 cm. Of course, these dimensions may vary greatly depending onthe clinical application, the amount of solution to be delivered andpossibly the distance from the surgical incision to the targeted tissue.Nozzle assembly 30 and its components are preferably comprised of abiocompatible material, preferably a plastic such as polycarbonate.Nozzle assembly 30 may be integral with or releasably coupled to thepropulsion device.

[0095]FIG. 2B illustrates one configuration of the nozzle assembly 30 ofFIG. 2A. Ampule body 32 defines an ampule reservoir 34 therein.Reservoir 34 preferably has a volume sufficient to hold at least onedose of an agent or solution, but may have any size volume toaccommodate any number of appropriate doses for a given application. Thedistal end portion 35 of reservoir 34 (approximately the most distal 10)of reservoir 34) has a distally tapered configuration that terminates ina single reservoir orifice 36. The diameter of reservoir orifice 36 iswithin the range from about 1.1 mm to about 1.3 mm. Proximal to distalend portion 35, reservoir 34 has a diameter in the range from about 0.75cm to about 1 cm. Although only ampule reservoirs having a singlereservoir orifice are illustrated in the drawings, the present inventionincludes ampule reservoirs configured to comprise more than onereservoir orifice.

[0096] The proximal end 60 of nozzle body 32 has a flanged configurationhaving mounting flanges 62 for mating with corresponding flange recessesof the distal end of an injection system (not shown) of the kindsdescribed with reference to FIGS. 1A and 1B. FIG. 3, for example,illustrates a corresponding mating configuration with flange recesses 72at the distal end 74 of an injection system 70 having a general designsimilar to that of the external ampule embodiment of FIG. 1A. Thismating configuration is some times referred to as a bayonet mountconfiguration.

[0097] At the distal end 38 of ampule body 32 is mounted an end effector40 in the form of a dispersion fixture or cap, having a generallycircular shaped distal portion 44 and an annular wall portion 46. Distalportion 44 has a smooth, generally planar, distal target-facing surface45. Distal portion 44 may also have a constant, downward grade (notshown) of approximately 3% from its perimeter to its center. Thisprovides a slightly concave surface to match that of the tissue surfacein order to ensure equidistance between each of the dispersion orifices(discussed below) and the tissue surface, and if so desired, to maximizecontact between target-facing surface 45 and the tissue surface.Optionally, a suction mechanism associated with ampule body 32 may beemployed to apply a negative pressure to the surface of the tissue inorder to help position end effector 40. The perimeter 48 of the outersurface of distal portion 44 is beveled so as to be atraumatic to thetissue if target-facing surface 45 comes into contact with tissue.Dispersion fixture 40 has an external diameter in the range from about1.75 cm to about 1.9 cm, and an internal diameter in the range fromabout 1.3 cm to about 1.6 cm.

[0098] Distal portion 44 also has a plurality of spaced-apart dispersionorifices 37 bored through the entire thickness of distal portion 64.Although not necessary for the performance of dispersion fixture 40,dispersion orifices 36 have a slightly distally tapered configuration attheir distal end to facilitate delivery of solution there through. Here,four dispersion orifices 37 are shown (see FIG. 2A) but any number ofdispersion orfices may be employed with the present invention.Dispersion orifices 37 are oriented in a quadrangle configuration toevenly disperse the injectate over or within a relatively broad area ofthe targeted site; however, any appropriate arrangement of thedispersion orifices, whether symmetrical or asymmetrical, and anyappropriate spacing between the orifices may be employed with thepresent invention. Other possible orifice configurations are discussedbelow with reference to FIGS. 6A-E.

[0099] At least one reservoir orifice and at least one dispersionorifice are necessary for the proper functioning of the injectionsystems of the present invention. However, an end effector employing oneor more dispersion orifices may be used with only a single correspondingreservoir orifice. Alternatively, a one-to-one correspondence betweendispersion and reservoir orifices may be employed. In fact, any suitablenumber of dispersion orifices may be used with any suitable number ofreservoir orifices.

[0100] As it is preferable to maintain a continuous, uninterrupted fluidcommunication between the reservoir orifice(s) and the correspondingdispersion orifice(s), the present invention may also include the use offluid pathways or channels between the dispersion and reservoirorifices. These pathways are preferably integral with either the ampuleor the end effector of the present invention.

[0101] As is more clearly illustrated in FIG. 2C, channels 52 are milledor machined within the distal surface 54 of ampule body 32. Dispersionorifices 37 terminate proximally at channels 52, respectively (discussedmore thoroughly below with respect to FIGS. 5A and 5B). Channels 52define the delivery pathways through which a solution is caused totravel as it is ejected or expelled from reservoir orifice 36. Thesolution is then caused to flow through and be ejected from respectivedispersion orifices 37.

[0102] Turning to FIG. 5, there is shown a cross-sectional view ofampule body 32 of FIG. 2A which more clearly illustrate the location andconfiguration of channels 52 within distal surface 54. Here, ampule body32 is coupled to another embodiment of a dispersion fixture 96.Juxtaposed between and in sealing engagement with the annular wall 95 ofdispersion fixture 96 and ampule body 32 is an annular sleeve 50 forproviding a fluid-tight seal to prevent against leakage of the solutionheld within ampule reservoir 34. Annular sleeve 50 has a wall heightequivalent to that of annular wall 95, and external and internaldiameters suitable for annular sleeve 50 to be fit snuggly betweenannular wall 95 and ampule body 32. Fixture 96 has dispersion orifices98 having a configuration different from that of the dispersion fixture40 of FIG. 2B, and which will be more thoroughly discussed below withrespect to FIGS. 4C and D.

[0103] Turning now to FIGS. 4A-D, the details of another embodiment of adispersion fixture 43 are illustrated. FIG. 4A shows the distal portion58 of dispersion fixture 43 having four dispersion orifices 42 boredthrough the entire thickness of distal portion 47. The cross-sectionalcutaway view of FIG. 4D shows each orifice 42 having a proximal portion42 a, a central portion 42 b and a distal portion 42 c. Proximal portion42 a has a cylindrical configuration having a diameter in the range fromabout 1.0 mm to about 1.3 mm. Central portion 42 b also has acylindrical configuration having a diameter in the range of about 0.1 mmto about 0.6 mm, and more preferably in the range of about 0.1 mm toabout 0.3 mm. Distal portion 42 c has a cone-like configuration with thenarrow end adjacent to and contiguous with central portion 42 b, andflaring to a diameter that is approximately twice that of centralportion 42 b. This orifice configuration provides a wider range ofdispersion, preferable when targeting larger areas of tissue.

[0104] Other suitable orifice designs are contemplated for use with thesurgical injection systems of the present invention. The cross-sectionalcut-away view of FIG. 4E shows one such alternate design. Here,dispersion fixture 49 has a dispersion orifice 80 bored through theentire thickness of dispersion fixture 49. Orifice 80 has a funnel shapecross-section, ending in a tubular distal portion 80 a having a diameterin preferably in the range from about 0.1 mm to about 0.3 mm. The lengthof tubular distal portion 80 a is approximately 2 to 5 times greaterthan the diameter. This design is more suitable when dispersing solutionin a smaller area of tissue.

[0105] Another embodiment of the solution channels of the presentinvention is seen in FIG. 4B, illustrating the underside 51 of distalportion 44 of dispersion fixture 43. Here, the channels 57 are cut ormilled within the dispersion fixture itself. Milled to a depth of about0.5 mm, channels 57 intersect at a central focal point 56 that isconcentrically aligned with the reservoir orifice of an ampule body (notshown). Channels 57 extend radially outward and terminate, respectively,at a corresponding dispersion orifice 42.

[0106] As is more clearly illustrated in FIGS. 4D and 4E, positionedwithin the proximal portion 42 a of each orifice 42 is a jewel orcrystal 66 having a disk configuration with a central bore 67. Jewel 66is preferably made of a hard material that can be precisely cut to forma uniform exit path for an ejected solution. Suitable materials includestainless steel or precious stones, such as sapphire or ruby. Althoughnot necessary for the proper functioning of dispersion fixture 43, ajewel is preferably used to ensure an accurate and precise vector pathof an ejected solution. Each jewel has a diameter sufficiently sized toallow jewel 66 to be press-fit into jewel chamber during the assemblyprocess. Central bore 67 preferably has a diameter from about 10 toabout 15 the diameter of jewel 66. Thus, when cap 43 and ampule body 32are assembled, channels 57 define the delivery paths through which asolution is caused to travel as it is ejected or expelled from areservoir orifice. From the respective channels 57, the ejected solutionis then caused to flow through central bore 67 of respective jewels 66,and then through and ejected from respective dispersion orifices 42.

[0107] As mentioned above, any suitable dispersion orifice, reservoirorifice, and channel configuration and pattern are contemplated for usewith the present invention. The particular dispersion orifice (andreservoir orifice) configuration to be used may depend on severalfactors including the medical condition being treated, the grossmorphology of the tissue area or other target site being treated, thetype of access provided for delivery of the device and the viscosity anddispersion characteristics of the injectate. For example, from what iscurrently known about angiogenesis, a better angiogenic outcome is morelikely where the angiogenic solution has at least some healthy tissue inwhich to initiate the grown of new vessels. Thus, in the case ofmyocardial infarction, the angiogenic solution is preferably injected,at least in part, into some healthy tissue immediately adjacent theinfarcted area. The particular orifice configuration will likely dependon whether the infarct is a subendocardial infarct or a transmuralinfarct. Subendocardial infarcts are characterized by multifocal areasof necrosis within the myocardium and are typically confined to theinner 12 of the myocardial wall, whereas a transmural infarct involvesthe entire thickness of the myocardial wall from endocardium toepicardium.

[0108] The quadrangle configuration of the dispersion orificesillustrated in FIG. 4A may be more suitable for a subendocardial infarctthan for transmural ischemia. The quadrangle configuration will likelycreate a contiguous, relatively expansive dispersion area in themyocardium, allowing the injected angiogenic solution to disperse withinthe outer layers of healthy tissue confining the subtransmural ischemia.In the case of transmural ischemia where the hypoxic tissue spans theentire thickness of the myocardium, leaving no healthy tissue at theepicardial or endocardial surfaces, injecting the angiogenic solutionwithin the perimeter of and directly over (epicardially) the infractedarea (or directly under the infracted area in the case of anendovascular approach) is not likely to produce the best results. A moresuitable dispersion fixture for this application is, for example, onehaving a single orifice, a linear array of orifices having a in anannular configuration (e.g., any shape ring or loop, or an archconfiguration) or a straight row(s) of orifice which can be selectivelyaligned with or immediately proximal to the perimeter of the ischemicarea wherein at least some of the angiogenic solution is dispersedwithin healthy tissue.

[0109] FIGS. 6A-E illustrate a few exemplary dispersion fixtures of thepresent invention having various shapes, sizes, orifice patterns andcorresponding channel configurations. Unless specifically referenced,certain dimensions (such as diameter and angle of curvature) of thevarious dispersion fixtures to follow should be assumed to beappropriately analogous to those of previous embodiments, keeping inmind the obvious variances attributable to the specific shape andnecessary surface area of the various dispersion fixtures.

[0110]FIG. 6A illustrates the underside of a dispersion fixture 104 ofthe kind discussed above with respect to FIGS. 2A-C. Here, the orificeconfiguration includes twelve (12) orifices 106 aligned in a ring closeto the perimeter of orifice fixture 104. The spacing between adjacentorifices 106 is the same throughout the ring. Corresponding to eachorifice 106 is a channel 108 extending radially from the center 110 ofdispersion fixture 104. This particular design is advantageous forinjecting an angiogenic solution to treat a transmural infarct, forexample. In use, the user would position dispersion fixture 104(attached to an injection device) on the patient's myocardium such thatorifices 106 surround the infracted area or are in close proximity tothe perimeter of the infracted area. As mentioned above, the presentinvention includes embodiments of dispersion fixtures having any numberof orifices arranged in any suitable pattern.

[0111]FIG. 6B illustrates the underside of another embodiment of adispersion fixture 112 having a circular shape and having a plurality ofdispersion orifices 114 in a staggered configuration which defines achannel pattern of two sets of symmetrical channels, channel set 116 a(the more proximal, set) and channel set 116 b (the more distal set)having different lengths, i.e., the channel length of channel set 116 ais shorter than that of channel set 116 b. This embodiment provides amore even distribution of injected solution in a defined area, and wouldbe useful, for example, in delivering angiogenic solution to an area ofmyocardium affected by a subtransmural infarct. Due to the shorterdistance from the center of the dispersion fixture 112, the pressure andvelocity of the injectate through the dispersion orifices 114 of channelset 116 a will likely be slightly greater than that being deliveredthrough the dispersion orifices 114 of channel set 116 b. However, thesize and path length (e.g., by means of curving) of one channel set maybe increased or decreased to compensate for the slight deviation.

[0112] Referring now to FIG. 6C, there is shown the underside of adispersion fixture 118 having an oval profile. As with the embodiment ofFIG. 6A, the dispersion orifices 120 are similarly aligned close to theperimeter of fixture 118; however, the resulting oval pattern oforifices 120 results in varying lengths of channels 122. Similar to theembodiment of FIG. 6B, the varying channel lengths will result incorrespondingly varying pressures, velocities and volumes of solutionexiting each orifice 120. Continuing to use the example of myocardialinfarcts, dispersion fixture 118 is more suitable for infarcted areasthat have a shape and size corresponding to that of fixture 118. Clearlythe distal end of a nozzle body to be used with dispersion fixture 118necessarily has a design and structure different from that of thepreviously discussed embodiments. Those skilled in the art willunderstand these necessary design modifications.

[0113]FIG. 6D illustrates the underside of yet another possibleembodiment of a dispersion fixture 124 of the present invention. Here,dispersion fixture 124 has a shape in the form of a diamond or of anarched cone. Five dispersion orifices 126 are aligned in a single,linear array proximate the perimeter of and matching the angle ofcurvature of annular or arched side 128 of dispersion fixture 124. Theincluded angle 125 at the vertex 123 of dispersion fixture 124 may rangefrom a minimum value, defined by the space necessary to accommodate asingle dispersion orifice, preferably greater than about 5(, to amaximum value of 360(, such as in the embodiments of FIGS. 6A-C. Moretypically, angle 125 will ranged from about 20(to about 180(, and evenmore typically, between about 45(and about 90(, such as with theembodiment of FIG. 6D. Here, dispersion orifices 126 are equidistantfrom the focal point 129 of dispersion, and thus, result incorresponding channels 130 which extend radially outward from focalpoint 129 and which have identical lengths. As with the embodiment ofFIG. 6A, the pressure, velocity and volume of solution exiting eachdispersion orifice 126 will be the same for each. Again, the requisitenozzle body design to be used with dispersion fixture 124 will differfrom those previously discussed. Those skilled in the art willunderstand the necessary design features required for a compatiblenozzle body.

[0114]FIG. 7A shows a cross-section front view of another embodiment ofa dispersion fixture 132. As is more clearly shown in the magnifiedbottom view of FIG. 7B, taken along the lines B-B in FIG. 7A,target-facing surface 138 of dispersion fixture 132 has an atraumatic,elliptical profile having a length preferably in the range of about 7 mmto about 10 cm and a width in the range of about 2.5 mm to about 4 cmbut will vary depending on the target organ or tissue and the size ofthe tissue area being treated. Target-facing surface 138 provides alinear array of dispersion orifices 134 in fluid communication withtheir respective channels 136 which, except for the center orifice, areat varying acute angles to tissue surface 133 when operativelypositioned. Such a dispersion fixture configuration is useful, forexample, for delivering an angiogenic solution to the epicardium alongor lateral to a portion of a coronary artery 135 affected byatherosclerotic plaque 143. In the latter case, an angiogenic solution,such as BFGF, may be used to promote the growth of collateral bloodvessels. This embodiment is also suitable for delivering a solution(such as ethanol) to the epicardial tissue, such as on the atria, forcreating a linear lesion to treat atrial fibrillation.

[0115] Additionally, as seen in FIG. 7A, target-facing surface 138 has ashallow arch configuration so as to maximize contact with the tissuesurface 133. Due to the slightly varying lengths of channels 136, thepressure, velocity and volume of solution exiting each dispersionorifice 134 will be slightly different. More specifically, the value ofthese variables will be the greatest for solution exiting the centerorifice and the lowest for solution exiting the two outermost orifices.The value of these variables for solution exiting the two orificespositioned in between the central and outermost orifices fall somewherein between the other two sets of values.

[0116] The construct of a nozzle body 140 compatible with dispersionfixture 132 of FIG. 7A is generally the same as that discussed withrespect to the nozzle body embodiment of FIG. 2B; however, the means forfunctionally attaching dispersion fixture 132 to nozzle body 140, andthereby functionally connecting reservoir orifice 142 to channels 136,is different. Such a means is generally referenced as 144 and includes alength of malleable tubing 145 extending from the very distal end 147 ofnozzle body 140 to the proximal end 137 of dispersion fixture 132.Tubing 145 transports a pressurized solution from within ampulereservoir 141 to channels 136, respectively, while providing a freerange of motion and positioning of dispersion fixture 132 relative tonozzle body 140. Tubing 145 is preferably comprised of material(s) thatallows it to be malleable. One suitable material is coated wire mesh,which is flexible enough to be contorted and bent but ridged enough toprovide stability and to reliably maintain the position of dispersionfixture 132 while solution is being injected into tissue. Tubing 145 mayeither define its own lumen 146 or encase a catheter (not shown)co-axially running at least the length of tubing 145. Such a catheter iscoupled to reservoir orifice 142 at its proximal end and to channelentrance 139 at its distal end. Tubing 145 and or a co-axial catheterare comprised of material(s) which provide a wall strength sufficient tomaintain the pressure and velocity of an injectate being deliveredthrough it. The attachment and connecting means 144 just described isnot limited to this embodiment but may be employed with any embodimentof the present invention.

[0117] Another feature of dispersion fixture 132 that is distinguishablefrom those previously discussed, is that a single jeweled substrate 148may be used in lieu of multiple jewels, one for each dispersion orificeas described for the previous embodiments. Jeweled plate 148 iscomprised of any suitable stone or crystal that would be used for themultiple jewel embodiments. As more clearly illustrated in FIGS. 7B, thebottom view of target-facing surface 138, the magnified top (or bottom)view of jeweled plate 148, and the cross-sectional side view of jeweledsubstrate 148, jeweled substrate 148 has a plurality of bores 150corresponding to the number of and aligned with dispersion orifices 139.A single substrate has the advantage of being easier to fabricate andeasier to handle and position within dispersion fixture 132 during themanufacturing process.

[0118]FIG. 7E illustrates an alternative configuration of a jeweledsubstrate 152. Jeweled substrate 152 has a narrow stem portion 154having a plurality of outposts 155 along one side of stem portion 154.Each outpost 155 has a jewel 156 attached to its distal end. Substrate152 and outposts 155 may be made of the jewel material being used oranother rigid material. One skilled in the art will recognize that othersuitable embodiments of the jewel piece(s) may be used with the presentinvention.

[0119] Although certain dispersion fixtures have been described for usein surgical applications, one skilled in the art can appreciate thatother shapes and sizes of dispersion fixtures and any number andconfiguration of orifices may be employed with the present invention.For example, a dispersion fixture of the present invention having arelatively small target-facing surface and only a single dispersionorifice may be useful for accurately and precisely delivering solutionto small, discrete areas of tissue, such as an area of infarctedmyocardium having diffuse locations of ischemia. An embodiment having adispersion fixture that is comprised of a relatively flat, thin,malleable sheath may be useful to treat oddly shaped or difficult toreach tissue, say for example, the back side of the liver or a tumorwithin the intestinal area whose dimensions and shape are not readilyknown until exposed.

[0120] The examples illustrated and discussed are not intended to limitthe invention. Those skilled in the art will appreciate that the mostuseful and appropriate dispersion fixture configuration for a particularclinical application may be dependent on a variety of factors, includingbut not limited to, the location of the organ or tissue being targeted,the size and depth of the area being treated, and the condition beingtreated.

[0121] The methods of using the injection systems of the presentinvention in a surgical setting will now be discussed with reference toFIGS. 8A-D. FIGS. 8A-D illustrate various embodiments of injectionsystems of the present being used in a thoracic or cardiothoracicsurgical application, for example, to deliver and inject angiogenicgrowth factor for initiating angiogenesis within the myocardium orwithin a coronary vessel. Typically, the solution delivery procedure inthe context of an open cardiac surgical procedure will be adjunct to aCABG or valve replacement or repair procedure. Also, the solutiondelivery procedure may be performed prior to or after the other surgicalprocedure and may be done on or off-pump.

[0122] Referring now to FIG. 8A, the patients chest is held open by asurgical retractor 212 while a surgeon 210 is holding a solutioninjection system 200 and targeting it on the myocardium of the patientshear 214. Solution injection system 200 has an injection portion 202,having a general structure in the form of a gun, and an ampule 204distally attached to injection portion 202. Ampule 204 holds theangiogenic solution to be delivered. Attached distally to ampule 204 isa dispersion fixture 206 in the form of cap similar to the embodiment ofFIGS. 2A-C. Here, dispersion fixture 206 is shown being held against andin direct contact with the epicardium in an area of infarcted tissue 216(outlined in phantom); however, direct contact is not required forperforming the methods of the present invention with any of the devicesof the present invention. In fact, depending on the application at hand,patient anatomy and surgeon preference, holding the injection system 200such that dispersion factor 206 is a selected distance (possibly as faras 2 cm) from the surface of the tissue may be preferable to directcontact. To ensure greater accuracy of positioning, a robotic mechanismmay be used. In either case, after providing a solution delivery device200 with ampule 204 filled with a selected volume of solution and withthe pressure gradient of the injection mechanism set at the desiredlevel, the dispersion fixture 206 is positioned adjacent or proximate tothe target tissue area. The propulsion mechanism (such as the onesdiscussed above with respect to FIGS. 1A and 1B) internal to injectionportion 202 is activated by means of a trigger mechanism (not shown) toprovide the requisite force to drive the solution out of ampulereservoir 204, into and through dispersion fixture 206 having a suitablesize and shape for the application at hand. The internal configurationof dispersion fixture 206 channels the solution flow through a definedpath or paths which optimize the volume and pressure of solution beinginjected at the desired point(s) within the target area. Upon injectioninto the target area, the highly pressurized injectate is then dispersedthroughout the selected area. This procedure may be repeated asnecessary for treating one or more targeted sites.

[0123]FIG. 8B illustrates use of solution injection system 215 of thepresent invention to treat a portion of myocardium 210 affected bysubendocardial ischemia. As the affected area 212 involves ischemictissue 212 within the central portion of the myocardium 210, thedispersion fixture 218 of solution injection system 215 is preferably ofthe type illustrated in FIGS. 2A-C and 4A-E. Operatively positioned onepicardium 214, this configuration allows for the jet delivery ofangiogenic solution into the healthy layer of tissue directly overischemic area 212. This allows for the angiogenic growth factors toinitiate the creation of new vessels within the healthy area.

[0124]FIG. 8C illustrates use of another injection system 220 of thepresent invention for the treatment of a portion of myocardium 222affected by a transmural ischemic area 224, wherein the affected area224 spans the thickness of myocardium 222 from endocardium 226 toepicardium 228. Solution injection system 220 has an ampule body 221housing reservoir 223 with a dispersion fixture 230 mounted thereto.Preferably, dispersion fixture 230 is of the type illustrated, forexample, in FIG. 6A, wherein a plurality of dispersion orifices 232arranged annularly and proximate to the perimeter of dispersion fixture230. The diameter of the annular configuration formed by dispersionorifices 232 is preferably slightly greater than the diameter ofinfracted area 224 (assuming the infarct has a generally annular shapeitself, otherwise, a more appropriate shaped dispersion fixture shouldbe used). Thus, with this embodiment, the angiogenic solution isinjected into or dispersed to at least some of the healthy tissueproximate the perimeter 225 of ischemic area 224 so as to further ensurethe genesis of new blood vessels.

[0125]FIG. 8D illustrates use of yet another injection system of thepresent invention. This embodiment has a dispersion fixture 234 havingthe configuration of the type illustrated in FIG. 6D, which is alsosuitable for use in treating an ischemic area 250 of a heart wall 252created by a transmural infarct. FIG. 8D provides a cross-sectional topview of dispersion fixture 234 illustrating an annular array ofdispersion orifices 236 aligned along and proximate to the perimeter ofarched portion 235 of fixture 234. Here, dispersion fixture 234 iscoupled to a rigid shaft 242 that extends form an ampule body (notshown). Fixture 234 and shaft 242 are preferably coupled by ahinged-type joint mechanism 243 (not shown in detail) that allowsdispersion fixture 234 to be selectively pivoted and locked in placewith respect to shaft 242. Dispersion fixture 234 has a range of motionpreferably from about 30(to about 110(with respect to the longitudinalaxis of shaft 242. This range of motion allows a user more flexibilityto treat difficult to reach tissue areas, such as on the posterior sideof the heart. Various configurations of such a joint mechanism arecommonly known by those skilled in the art.

[0126] Running coaxially with the lumen of shaft 242 is flexible tubing240 that provides a conduit for transporting a pressurized solutionbetween an ampule reservoir (not shown) and dispersion fixture 234.Tubing 240 is flexible enough and has sufficient slack along its lengthto allow for the variable positioning of dispersion fixture 234 withrespect to shaft 242. Tubing 145 is preferably comprised of high tensilestrength plastic or silicone reinforced with stainless steel ribs orwound wire in order to maintain a desired solution pressure and velocitythroughout the injection cycle. Distal end 244 of tubing 240 terminatesat an opening to the entrance of solution channels 238 each of whichextend radially to a respective dispersion orifice 236

[0127] When using embodiments of the present invention having dispersionmeans with flexible, malleable or otherwise variable components, such asthose described with respect to FIGS. 7A and 8D, the physician or otheruser, prior to each injection, will have the option to adjust theposition of the dispersion means with respect to the injection device tooptimize the delivery and dispersion of a solution. This includes eitheradjusting (e.g., bending, angling, etc. as appropriate) the dispersionfixture, or the means for coupling the dispersion fixture to the ampule,or both. These configurations of solution delivery devices may also beuseable in less invasive surgical procedures, such as those describedbelow.

[0128] Although only several embodiments of injection systems forsurgical applications have been illustrated and described, those skilledin the art will appreciate the modifications and variations that can bemade to these devices to suit a particular application. As mentionedabove, the most appropriate dispersion fixture configuration for aparticular clinical application will depend on several factors,including but not limited to, accurately assessing the condition to betreated (e.g., subendocardial ischemia vs. transmural ischemia), thesize, shape and thickness of the tissue area being treated, the depth ofthe area from the tissues surface, the location of the treatment area(i.e., the organ being targeted), and the ease of access or lack thereofto the targeted locations. Additionally, the most appropriate dispersionorifice configuration, including the number of orifices, the size of theorifice(s) and the arrangement of orifices, will depend on severalfactors, including but not limited to, the pressure profile of thepropulsion device being used, the viscosity of the injectate, and thesize of the surface area of the target site.

[0129] The present invention can also be configured for delivering asolution to a targeted site within the body in the context of a lessinvasive surgical procedure. The means of access for less invasivesurgeries, particularly for a minimally invasive cardiac surgery, istypically accomplished by means of a very small incision or a positionedthrough the skin. For minimally invasive cardiac surgery, the port iscreated within the patients chest cavity or through a mini-thoracotomyor other minimally invasive incision in the chest area. A port accessapproach may require the use of a trocar, an elongated tubular devicethat provides a conduit from outside the body to the target area withinthe body. A larger but still less invasive incision may not require useof a trocar but may still require the use of smaller and preferablyflexible or malleable tools to access the more difficult to reach areas.Still other less invasive procedures involve the use of an endoscope tofacilitate visualization while performing the surgery.

[0130] The injection devices described above for use in the injectionsystems of the present invention for direct surgical applications arealso suitable for use in injection systems for less invasive surgicalapplications. It is the configuration of the dispersion means of theless invasive systems, as defined by the particular end effector beingused, which necessarily has a slimmer or lower profile than those of thesystems for surgical applications. The specific design of the endeffector for a less invasive surgical approach will primarily depend onsuch factors, including but not limited, the location of the treatmentarea (i.e., the organ being targeted) and the ease of access or lackthereof to the treatment area. For example, accessing an area of tissueon the myocardium through a port between a patient's ribs may require adifferent configuration than accessing a portion of intestine in alaparoscopic procedure. Particularly in the case of a cardiac procedure,the configuration of the dispersion means may also depend on whether thesolution delivery procedure is adjunct to another procedure, such as aCABG or a valve repair or replacement procedure, or is the soleprocedure being performed. In the former situation, the pericardium willhave been incised to access the heart, possibly requiring only minormodifications to the dispersion means of the present invention, some ofwhich are described below. On the other hand, in the latter situation,it may not be necessary to cut into the pericardium. For example, asolution (e.g., such as an antibiotic for the treatment of pericarditisor myocarditis) may be injected with the present invention directlythrough the pericardium so as to fill the pericardial space (i.e.,intrapericardial injection) for prolonged exposure to the pericardium orthe myocardium. Alternately, a solution (e.g., such as an angiogenicsolution for treating ischemic myocardial tissue), may be injected withsufficient pressure so as to penetrate both the pericardial sac. and themyocardium with the solution.

[0131] Turning now to FIGS. 9 and 10, exemplary configurations of endeffectors of the present invention are illustrated in use in the contextof a less invasive cardiac procedure, such as for the treatment of anarea of ischemic tissue by means of high-pressure injection of anangiogenic solution into the target tissue. FIG. 9 is a view of a heartfrom within the thoracic cavity and an embodiment of a dispersion means260 operatively positioned to treat an area of the myocardium 254.Dispersion means 260 includes a cylindrical shaft 261 coaxiallypositioned within a trocar port 265 operatively positioned between twoadjacent ribs 256. Trocar ports suitable for use in this and otherthoracic procedures are commonly known to those skilled in the art ofcardiac and thoracic surgery. Dispersion means 260 further includes adispersion fixture 262 attached to the distal end of shaft 261 shownhere to be in operative contact with a targeted area 258 of the heartsepicardium. Dispersion fixture 262 has a configuration generally similarto those illustrated in FIGS. 8A-C. However, here, dispersion fixture262 has a diameter (or other transverse dimension depending on the shapeof the fixture) small enough to fit through trocar port 265 and may haveany suitable shape and dispersion orifice configuration (similar tothose discussed above with respect to embodiments for surgicalapplications) for the application at hand. Shaft 261 defines an internalspace comprising either an ampule reservoir (not shown), similar tothose described above for surgical applications, or a lumen (not shown)for transporting solution from an ampule reservoir (located eitherproximally within shaft 261 or within the injection device itself) todispersion fixture 262. In the case where the ampule reservoir islocated within shaft 262, the reservoir has length and diameterdimensions suitable for being housed in shaft 261 and for defining avolume sufficient to hold at least a single dose of solution.

[0132] A method of using the embodiment of FIG. 9 will now be discussedin the context of a minimally invasive cardiac procedure in which asolution is being delivered to a target area 238 on the epicardium.After a small incision is made at the desired location (e.g., betweenadjacent ribs 256), trocar 265 is positioned within the incision.Dispersion means 260 is then inserted into the proximal end of trocar265 and moved coaxially within trocar 265 until dispersion fixture 262is delivered to a desired distance from or in contact with the targettissue. With the ampule reservoir filled with the desired amount ofsolution and the injection mechanism of the injection system properlyset for firing, the system is actuated, causing the solution to beejected from the ampule reservoir and delivered through shaft 261 todispersion fixture 262. The dispersion orifices (not shown) thendirected the solution to various sites within the target area.

[0133] Turning now to FIG. 10, there is shown another embodiment of adispersion means 270 of the present invention in use in a less invasivecardiac procedure in which access to the heart is accomplished throughan opening made, for example, in the region just below the patient'sxyphoid 280 (i.e., subxyphoid). Dispersion means 270 comprises amalleable catheter or tubing 274 which, at its proximal end, is insealing engagement with the orifice of an ampule reservoir (not shown),and extends distally to dispersion fixture or catheter tip 275. Tip 275has at least one dispersion orifice. In the application illustrated inFIG. 10, only a single dispersion orifice is employed, and is preferablylocated so as to provide a solution path, which remains coaxial withcatheter 274 after exiting the dispersion orifice. However, anyappropriate number of dispersion orifices having any suitable shape andsize and located at any suitable location on the tip region of thecatheter is contemplated. The location of such orifices is discussedmore thoroughly below in the discussion of endovascular devices of thepresent invention. Tubing 274 is preferably comprised of a strong yetflexible medical grade material, such as nitinol, nylon, or polyimidereinforced with stainless steel or Kevlar, and may have any suitablelength for the application at hand. Tubing 274 has outer and innerdiameters suitable for connection to an ampule reservoir orifice and forcoaxial alignment within a cannula or tubing 278.

[0134] In FIG. 10, a port 272 has been positioned within a subxyphbidincision, for example, to provide access to within the thoracic cavityof the patient. This port configuration is more suitable for penetrationthrough the diaphragm 282 rather than between the ribs such as trocar235 of FIG. 9. A flexible, steerable cannula or tubing 278 extendsproximally from and is in sealing engagement with port 272. Tubing 278is preferably comprised of material mentioned above with respect totubing 274 of FIG. 10, and may have any suitable length for theapplication at hand.

[0135] A method of using the embodiment of FIG. 10 will now be discussedin the context of a minimally invasive cardiac procedure in which asolution is being delivered to a target area 284 on the epicardium.After a small incision is made at the desired location in the subxyphoidregion, port 272 and the attached cannula 278 are positioned within theincision. Tubing 274 is shaped into a desirable configuration and theninserted into the proximal end of cannula 278. The malleability ofcatheter 274 allows it to be shaped in a configuration that will morereadily facilitate navigation of catheter tip 275 to the target area(s).The flexibility and deformability of cannula 278 allows it to complywith the shape of the catheter being inserted into it and furtherincreases ease of access to the target area(s). Catheter 274 is thensteered distally through cannula 278 until catheter tip 275 is deliveredto a desired distance from or in contact with the target tissue 284.With the ampule reservoir filled with the desired amount of solution andthe injection mechanism of the injection system properly set for firing,the system is actuated, causing the solution to be ejected from theampule reservoir and delivered through catheter 274 to the dispersionorifice at tip 275, which precisely directs the solution to a selectedsite within the target area 284. All or some of the steps of thisprocess may be repeated as necessary to deliver solution to other siteswith the same or different target area. Additionally, an endoscope and alight source, either integral with system of the present invention or asa stand-alone unit, may be used with the process just described in orderto facilitate visualization by the surgeon of the surgical area.

[0136] The flexibility and low profile of this embodiment allowssolution to be delivered to areas that are very difficult to reach,particularly through a less invasive incision. For example, as shown inFIG. 10, the device is capable of delivering solution to a target areaof tissue on the posterior side of the heart. Also, this configurationmay also be suitable for injecting a solution directly through thepericardial sac. Those skilled in the art will appreciate the diversityof this embodiment and the many applications for which it is suitable.

[0137] The dispersion means of the present invention for use inendovascular applications includes a catheter assembly having an endeffector in the form of a catheter tip to access a target site within anorgan, a tumor, a body or vessel lumen, or an artificial graft lumen.Some applications include, for example, accessing a target area on theinside surface of the heart (i.e., the endocardium), within the cardiacvasculature (such as the aorta, or a coronary artery or vein), withinthe peripheral vasculature (such as the iliac, femoral, popiteal andinfrarenal), within the neurovascular systems (such as the carotidartery) or to a tumor via the vasculature from which it receives itsblood supply. The endovascular approaches involve inserting a catheterof the present invention through a percutaneous incision made within avessel, such as the femoral artery, subclavian artery, the carotidartery or other suitable vessel, and delivering the catheter tip to atarget site by means of a guide wire (e.g. over-the-wire, rapid exchangeor monorail catheter guide wire configuration) or a guiding catheter,many of which are commonly used in the art. Such a catheter isconfigured for attachment to the distal end of an ampule (such as theembodiment of FIG. 1A) or directly to the distal end of an injectiondevice (such as the embodiment of FIG. 1B).

[0138] Turning again to the drawings, FIG. 11A illustrates an embodimentof a dispersion means 300 of the present invention for use inendovascular applications. Dispersion means 300 includes catheterassembly 304 integrally coupled to an ampule body 308 defining areservoir 310 by means of a retainer 311 threaded over the distal end309 of ampule body 308. Proximal end 307 of ampule body 308 defines abayonet mount for coupling to the distal end of an injection system(such as injection system 10 of FIG. 1A).

[0139] Retainer 311 generally has a similar shape and size as thedispersion fixtures discussed above with respect to the intraoperativedevices illustrated; however, retainer 311 does not provide a solutiondispersion function but, instead, provides a means for securelyretaining the attachment of catheter assembly 304 to ampule body 308,particularly during an injection cycle. Juxtaposed between and inengagement with retainer wall 303 of retainer 311 and ampule body 308 isan annular sleeve 305, which further ensure retention of catheterassembly 304 to ampule body 308 when under the high pressures of aninjection cycle.

[0140] Another difference between this endovascular device and thesurgical devices discussed above is the configuration of distal portion309 of ampule body 308. As is more clearly illustrated in thecross-sectional view of FIG. 11B, distal portion 309 terminates in anannular wall 312 and a reservoir nozzle 313 extending from reservoirorifice 316. Reservoir nozzle 313 is centrally and coaxially positionedwithin annular wall 312, and both extend about 7.5 mm proximally ofampule body 308, and collectively define a toroidal shaped space 315between them. Reservoir nozzle 313 has a centrally disposed, narrowlumen 314 in fluid communication with reservoir orifice 316. Narrowlumen 314, as well as reservoir orifice 316, has diameters in the rangefrom about 0.4 mm to about 0.8 mm.

[0141] Catheter assembly 304 includes a catheter 318 attached proximallyto a coupler 320. Catheter 318 is comprised of material(s) havingcolumnar and wall strengths sufficient to maintain the desired pressureand velocity of an injected solution throughout the injection cycle.Here, for added performance, catheter 318 is preferably comprised of twolayers, an internal conduit 321 preferably made of a braided polyimidefor strength, and an outer sheath 322 preferably comprised ofthermoplastic polyether-based polyamide (PEBAX) which provides a softatraumatic feel.

[0142] The length and diameter (or size in French units) of catheter 318will depend on the diameter of the vessel providing the delivery pathand the distance between the percutaneous entry site and the targetsite(s) (e.g., coronary artery, carotid artery, iliac artery, femoralvein, subclavian artery, cerebral artery, renal artery, etc.). Forexample, a catheter delivered through a percutaneous site in the femoralartery at the patients groin to location within the heart preferably hasa length within the range from about 1.3 meters to about 1.7 meters, andmore preferably a length of about 1.5 meters. A catheter to be deliveredto within a coronary artery, for example, likely has an outer diameterthat is smaller than that which is delivered to a heart chamber such asthe left ventricle, and is preferably is in the range from about 1.4 mmto about 1.8 mm, or a French size of about 4 to about 6. On the otherhand, if the target site is within an inferior portion of the femoralvein and the catheter entry site is within the portion of the veinlocated near the groin, a catheter having a shorter length and possiblya larger outer diameter may be used.

[0143] As mentioned above, catheter assembly 304 further comprises acoupler 320, such as a luer subassembly, for coupling catheter 304 intoreservoir nozzle 313. FIGS. 11C and D more clearly illustrate theconfiguration of luer subassembly 320, which generally includes a luerfitting 324 and hypotube 326 extending coaxially from the distal end 328of luer fitting 324. Luer fitting 324 is preferably comprised ofstainless steel. Luer fitting 324 preferably has a length within therange from about 20 mm to about 24 mm, and an outer diameter at thewidest portion of the luer wall 323 is in the range from about 6 cm toabout 8 mm. The cylindrical lumen 325 has a slightly distally taperedconfiguration within which it matingly receives and engages the distalend of reservoir nozzle 315. The profile of distal end 328 of luerfitting tapers somewhat and defines a luer shoulder 338.

[0144] Centrally disposed within distal end 328 of luer fitting 324,hypotube 326 is in fluid communication with luer lumen 325. Hypotube 326extends distally from its proximal end 330, flush with the distal end329 of luer lumen 325, to a flared distal tip 332. Like catheter 318,hypotube 326 is comprised of material(s) that can maintain the desiredpressure and velocity of an injected solution throughout the injectioncycle, and is preferably made of stainless steel. Hypotube 326 has alength preferably in the range from about 1.0 cm to about 1.3 cm, anouter diameter preferably in the range from about 0.5 mm to about 0.7mm, and an inner diameter preferably in the range from about 0.35 mm toabout 0.5 mm. As is more clearly illustrated in FIG. 11E, distal tip 332of hypotube 326 flares outward at a slight angle 334 in the range ofabout 6% to about 9% from the axis defined by the inside of the tubingwall. The flared portion of distal tip 332 comprises about 3 to about 5of the entire length of hypotube 326. The outer diameter at burnishededge 336 of flared tip 332 is approximately about 0.01 to about 0.2 mmgreater than that of the remainder of the hypotube 326. This tipconfiguration helps ensures a tightly sealed fit between hypotube 326and the proximal end of catheter 318. More specifically, flared tip 332and the distal portion of hypotube 326 are inserted into the lumen ofinner layer 321 at the proximal end of catheter 318, and then sealed toit by means of an epoxy. A short metal ferrule 340 (having a length justshy of the portion of hypotube 326 which extends from distal end 328) isthen fit over and crimped around the distal end of hypotube 326. Theouter layer 322 of catheter 318 is then slid over and sealed to theentire length of inner layer 321, including ferrule 340.

[0145] Turning now to the perspective view of retainer 311 in FIG. 11F,retainer 311 is preferably made of a polycarbonate material and has acentrally positioned bore through its closed end 344 beveled at itsperimeter 346. Retainer 311 is assembled with nozzle assembly 302 andcatheter assembly 304 by passing the distal tip 350 of catheter 318through the underside of retainer 311 and through bore 342. Retainer 311is then slide over catheter 318 and distal end 328 of luer fitting 324until close end 344 buttresses against luer shoulder 338. Bore 342allows retainer 311 to rotate around catheter assembly 304 while it isbeing manually screwed onto annular sleeve 305. As just described,catheter assembly 304 and nozzle assembly 302 are now securely engagedwith each other.

[0146]FIG. 11G shows a perspective view of another embodiment of aretainer 352 for use with the present invention. The configuration ofretainer 352 is generally similar to that of retainer 311 of FIG. 11;however, closed end 355 of retainer 352 has a keyhole shaped slot 354that runs the height of annular sidewall 356. With the slottedconfiguration, retainer 352 can be seated in place without having toslide retainer 352 over the entire length of catheter 318. Chamber 354is aligned along catheter assembly 304 just above distal end 328 of luerfitting 320. After proper alignment, retainer 352 is screwed ontoannular sleeve 305. Besides ease of use, this configuration has theadded advantage of avoiding potential damage to catheter 318 andparticularly catheter tip 350. Sidewall 356 is fluted for better grip.Retainer 352 is preferably comprised of aluminum or of anotherlightweight, rigid metal, rather than of a plastic material as theslotted configuration of retainer 352 makes it more susceptible tofailure under the injection pressure if made of plastic.

[0147] Various embodiments of catheter tips for use with theendovascular devices of the present invention will now be described anddiscussed. The particular design of a catheter tip and its target-facingsurface for use with the present invention will depend in part on thetype of treatment involved. Some applications include, for example,accessing a target area in a chamber or lumen within an organ, withinthe cardiac vasculature, the peripheral vasculature and theneurovascular systems, or on or in a tumor via the vasculature fromwhich it receives its blood supply. It is also intended that the variouscatheter tip embodiments be interchangeable with each for attachment tothe same catheter.

[0148] The catheter tip design, and more specifically the design of thetarget-facing surface of the tip, will also depend upon the location ofthe targeted site and the type of tissue or substance being treated. Forexample, when treating a coronary artery affected by artheroscleroticplaque, such as with an angiogenic solution to promote collateral vesselgrowth or with another solution such as inducible nitrous oxide synthase(iNOS) to reduce plaque or minimize the likelihood of restenosis, it ispreferable to use a catheter tip that is able to inject the solutiondirectly into or through the artery wall. As a catheter is typicallycoaxial with and parallel to a vessel lumen into which it has beendelivered, a suitable catheter tip for this application is preferablyone that is capable of directing the ejected solution along a path thatis lateral to the catheter wall and preferably somewhat transverse to,and possibly directly perpendicular to, the artery lumen. Thus, such adesign dictates that the target-facing surface, i.e., the portion of thetip comprising the dispersion orifices, comprise at least a portion ofthe wall of the catheter tip. Simply stated, such a tip design ejectsthe solution from the side of the catheter.

[0149] Referring now to FIG. 12, there is shown an exemplary embodimentof a side-shooting catheter tip for use with the catheter-based solutiondispersion means of the present invention. Catheter tip 400 is simply adistal extension of its catheter body sealed at its distal end 407,which facilitates atraumatic delivery of the catheter through thevasculature. Additionally, catheter tip 400 has a linear array of sixdispersion orifices 402 (formed by means of an exymer laser process)aligned in a single path along one side of catheter wall 404 (i.e., thetarget-facing surface) and parallel to the longitudinal axis of cathetertip 400. Any suitable number of dispersion orifices and array oforifices arranged in any suitable pattern (e.g., helically or in a solidpattern around the circumference of the catheter tip, etc.) may beemployed with the side-shooting catheter of the present invention. Thediameter of each dispersion orifice 402 is in the range from about 0.1mm to about 0.3 mm. The length of the orifice array path and thedistance between the orifices 402 will depend on the application at handand the surface area of the tissue site being treated. Here, dispersionorifices 402 are preferably spaced apart in the range from about 3 mm toabout 5 mm. As such, catheter tip 400 is configured, for example, totreat a site within a vessel affected by atherosclerotic plaque whereinthe plaque-covered area (i.e., the target site) is situated to theorifice side of catheter tip 400. This embodiment is also useful todeliver a thrombolytic agent to an area of thrombus within a vessel thatextends along a length of the vessel.

[0150] FIGS. 13A-B illustrate such a side-shooting catheter in atransvascular approach to treating a stenotic area within a cardiacvessel. By transvascular, it is meant that the target tissue orsubstance site is adjacent to or otherwise outside the vessel throughwhich the catheter is being delivered. Here, catheter tip 410, having adispersion orifice configuration 412 similar to that of catheter tip 400of FIG. 12, has been delivered endovascularly to within a vessel 415embedded within the myocardium, such as the cardiac vein, which issubstantially parallel with and lateral to coronary artery 417 having astenotic area 419. Here, the array of dispersion orifices 412 has beenpositioned along the side of cardiac vein 415 adjacent to the stenoticarea 419 within artery 417. Thus, a solution 414 ejected from orifices412 by means of a solution injection device of the present inventionwould define an injectate vector path substantially perpendicular to theaxis of catheter tip 410 and to the lumen wall of vein 415 and artery417, thereby targeting stenotic area 419.

[0151] Turning now to FIGS. 14A-B, there is shown another embodiment ofa side-shooting catheter tip 420 of the present invention in use in anintracoronary application. Catheter tip 420 has a plurality ofdispersion orifices 422 arranged in a dense, circumferential patternthroughout tip 420. In FIG. 14A, catheter tip 420 has been delivereddirectly to within coronary artery 425 and positioned just proximal tostenotic area 423, allowing a solution, such as an angiogenic solutionto be injected into the artery wall proximal of stenotic are 423.Ideally, collateral vessel growth is initiated in the myocardial bedsurrounding artery 425 to allow for enhanced blood flow to the tissues.

[0152] As is shown in FIG. 14B, catheter tip 420 may be delivered to thedistal side of stenotic area 423, provided that the diameter of thevessel lumen at stenotic area 419 is large enough for catheter tip 420to pass through without the risk of embolizing the plaque. Preferably,then, collateral vessel growth is initiated on both sides of stenoticregion 419 to further enhance blood supply to the myocardium and toreduce the risk of ischemia in case vessel. 425 becomes significantlyoccluded. If, however, stenotic area 419 is sufficiently occluded so asto make passage of catheter tip 420 to the distal side of stenotic area419 impossible or highly risky, a physician may choose to widen thepassage by means of a PTCA procedure prior to the step of deliveringcatheter tip 420 distal of stenotic area 419. In addition to injectingangiogenic drug into the wall of artery 425 proximally and distally ofstenotic area 419, the same or a different solution, such as anthrombolitic (such as tissue plasminogen activator (tPA)) or a genetherapy drug (such as inducible nitrous oxide synthase (iNOS)) may beinjected directly into stenotic area 419 itself. The latter injectionmay be accomplished by means of the same catheter used for delivery ofthe angiogenic solution, or by means of a second catheter. In eithersituation, a change of drug ampules may be required. It should also benoted that more than one type of solution or more than one injection ofthe same solution may be injected into the same target tissue site.

[0153]FIG. 15 illustrates another embodiment of a side-shooting catheterdispersion means of the present invention having angioplastycapabilities integrated therein. A dilation means in the form of aninflatable balloon 430 has been incorporated into the catheter tip 426for performing angioplasty at stenotic site 429. Balloon 430 is situatedbetween proximal and distal dispersion sections 431, 432. Dispersionsections 431, 432 have dispersion orifice configurations similar to thatof catheter tip 420 of FIGS. 12A-B but which extend over a length abouttwice that of catheter 420. This embodiment allows simultaneousdispersion of the treatment solution proximally and distally of stenoticarea 429 while eliminating the step of using a separate angioplastycatheter. Those skilled in the art will recognize ways in which thenecessary angioplasty components may be incorporated into the catheterdispersion means of the present invention.

[0154] The present invention includes another type of catheter tip thatis more suitable for injecting a solution into a targeted site locatedeither within or on an organ, a tumor or some other non-tubular tissuestructure, or within a vessel lumen but not necessarily within the wallof the vessel itself. More specifically, such a catheter tip design iscapable of ejecting a solution in a path distally of the catheter tipand substantially coaxial or parallel to the longitudinal axis of thecatheter. The dispersion orifice(s) for such a tip design is preferablylocated at the distally-facing end of the catheter tip rather thanthrough its sidewalls. Simply stated, such a tip design ejects thesolution from the end of the catheter.

[0155] Turning now to FIGS. 16A-C, an embodiment of such an end-shootingcatheter tip assembly 440 of the present invention will now be describedand discussed. Catheter tip assembly 440 includes a section of hypotube442 and a dispersion fixture or cap 446 at the coupled to the distal endof hypotube 442. Hypotube 442 has a flared proximal end 444 to ensure atightly sealed fit between it and the distal end of catheter 462 ofcatheter assembly 460 (see FIG. 16C). Hypotube 442 has the sameconfiguration and dimensions and is comprised of the same material ashypotube section 326 of FIG. 11D-E except that the flared end ofhypotube section 326 is its distal end rather than its proximal end.Dispersion fixture or cap 446 has a cylindrical configuration preferablyhaving a wall height in the range from about 1.8 mm to about 2.0 mm, anouter diameter in the range from about 1.5 mm to about 1.7 mm, an innerdiameter in the range from about 1.0 mm to about 1.2 mm. The distal endof dispersion cap 446 defines a distal surface 445, which in thisembodiment is flat but may have any appropriate shape (e.g., concave,rounded) for the application at hand. Distal surface 445 has adispersion orifice 447 centrally bored there through and having adiameter in the range from about 0.1 mm to about 0.6 mm, and morepreferably from about 0.1 mm to about 0.3 mm. Dispersion orifice 447 mayhave any suitable size and shape such as a circular bore, a slot, adiamond shape, etc. Additionally, any suitable number of orifices may beused.

[0156] Seated flush within dispersion cap 446 is jewel or crystal 448having a disk configuration with a diameter sufficiently sized to allowjewel 448 to be slip-fit into dispersion cap 446. Jewel 448 has acentral bore 449 having a diameter in the range from about 0.1 mm toabout 0.3 mm (about 30 to about 35 the diameter of dispersion orifice447), which is centrally aligned with dispersion orifice 447 and thelumen of hypotube 442 when jewel 448 is operatively seated. As with thejewels discussed with respect to the surgical embodiments discussedabove, jewel 448, although not necessary, is preferably used to ensurean accurate and precise vector path of an ejected solution. Coaxiallydisposed between dispersion cap 446 and the distal end of hypotube 442,and abutting the proximal side of jewel 448, is an annular sleeve 450.Annular 450 is preferably laser welded at points of contact between itand dispersion cap 446 and hypotube 442, respectively, to provide afluid-tight seal to prevent against leakage of a solution as it is beingejected and to retain jewel 448.

[0157] The cross-sectional view of FIG. 16C shows catheter tip assembly440 operatively coupled within the distal end of a catheter 460, whichpreferably has the same two-ply configuration as catheter 318 describedabove with respect to FIG. 11A. Here, internal conduit and outer sheathare referenced as 462 and 464, respectively. Similar to the manner inwhich hypotube 326 and the proximal end of catheter 318 of FIG. 11A arecoupled together, hypotube 442 is inserted into the distal end ofinternal conduit 462 over which a ferrule 468 is coaxially positionedand crimped. Outer sheath 464 is then sealed with epoxy around thiscomposite structure.

[0158] Endovascular methods of using such an end-shooting catheter ofFIGS. 16A-C include intrachamber and intravascular approaches. Theintrachamber approach involves delivering the catheter tip to within achamber or lumen in an organ. An intravascular approach involvesdelivering of the catheter tip to within a selected portion of an arteryor vein, such as a coronary artery, a peripheral vessel, or theneurovasculature.

[0159] Specific cardiac applications of the intrachamber approachinclude but are not limited to the delivery of an angiogenic solution tothe endocardium, such as within the left or right ventricle, fortreatment of an ischemic area of myocardium; the delivery of ananti-angiogenic solution to treat a tumor located within a heart chamber(i.e., a myxoma); the delivery of a biochemical, such as ethanol, towithin the atria for treating atrial fibrillation; and the delivery of athrombolytic solution, such as tPA, to break up a thrombus within theatria.

[0160] For example, FIG. 17 illustrates use of an endovasculardispersion means of the present invention having a catheter assembly 500including a catheter 502 and catheter tip 504, of the construction justdescribed with respect to FIGS. 16A-C. Catheter assembly 500 has beendelivered endovascularly to within a chamber of the heart, such as theleft ventricle, to treat an ischemic region 507 of the myocardium 505.Here, catheter tip 504 is shown operatively contacting endocardium 509for delivery of an angiogenic solution to the targeted tissue area 507.As mentioned above with respect to other embodiments of the dispersionmeans of the present invention, it is not necessary to contact thetarget area with the catheter tip; however, in this application, it maybe preferable as the flow of blood within the ventricle during thesystolic and diastolic cycle does not interfere with the delivery pathor reduce the pressure of the ejected solution prior to its entry intothe endocardium 509. Catheter tip 504 may be delivered to within anydistance from the surface of the endocardium which will allow thedelivery of a sufficient volume of solution at a desired pressure.

[0161] Specific cardiac applications of the intravascular approach usingan end-shooting catheter tip include but are not limited to the deliverya thrombolytic solution, such as TPA, or a non-drug such as saline, tobreak up a thrombus within the coronary, peripheral or a neurovasculature. More specifically, when the thrombus is more of a localizedformation, such as that in FIGS. 18A-B, rather than a planarconfiguration along a length of a vessel wall, the such an end-shootingembodiment is appropriate. For example, FIGS. 18A-B illustrate anintravascular approach of the present invention for treating deep veinthrombosis such as within the saphenous or iliac vein 512 of a patientsleg 510. Here, an embodiment of a catheter 520 having a multi-orifice,end-shooting catheter tip configuration 522 has been delivered through apercutaneous incision 514 proximate the patients groin to a locationjust proximal of the target site or thrombus 516 anchored to the innerwall of vessel 512. The end-shooting catheter tip 522 is designed todirect an throbolitic solution at the thrombus 516, but not directlyinto the tissue wall to which the thrombus is anchored, thereby avoidinginjuring to the vessel wall.

[0162] FIGS. 19A-B illustrate another example of an intravascularapproach of the present invention in a neurovascular application. FIG.19A is a cross-sectional view of a medial portion of a human brain 540.Here, an end-shooting catheter 530 has been delivered through apercutaneous incision (not shown) into the carotid artery of the patientand into the cerebral artery 542 to reach thrombus 544. Multi-orificecatheter tip 532 has been positioned just proximal of thrombus 544 whereit is ideally positioned to deliver the thrombolytic solution to thethrombus 544.

[0163] Another application of the endovascular embodiments of thepresent invention is the treatment of AV access grafts that have plaqueand/or thrombus formations within the graft lumen. Most commonly, theinjectate is a thrombolytic drug or a lysing agent. Similar to the otherintravascular applications discussed above, the treatment of AV accessgrafts involves inserting the catheter through a percutaneous openingand delivering the catheter tip proximate the target site, e.g., an areaof plaque or thrombus formation. Here, the percutaneous opening is mosttypically the external opening of the graft, but the opening may be apercutaneous incision through the skin at a location near the graft.Either a side-shooting or an end shooting catheter may be used,depending on the specific location and positioning of the formationbeing targeted. The therapeutic agent is then injected at the targetsite. As medically dictated, the targeted formation may be dissolved orbroken up sufficiently to be released systemically within the patient,or may otherwise be filtered or vacuumed and then removed from the graftby the physician.

[0164] A diagnostic application of the present invention, primarily theendovascular embodiments, involves first using the catheter to injectcontrast solution (prior to injecting a therapeutic solution) into thegeneral target site while examining the site under fluoroscopy. Thepurpose of this diagnostic step is to determine the landscape ofmicrovasculature in the target tissue site in order to avoid rupturingthe healthy microvasculature. Rupturing the microvasculature is clearlydamaging to the tissue and can also cause the injectate to enter theblood stream for systemic distribution that may be harmful to thepatient. From this diagnostic step, the practitioner may determine theappropriate injection penetration depth, and the appropriate size andnumber of dispersion orifices.

[0165] In order to effectively treat the affected area of tissue or thesubstance affecting the targeted tissue site with any embodiment and inany application of the present invention, it is important for thephysician or user of the present invention to be aware of potentialfactors that may affect the desired dispersion pattern of the injectate.By dispersion pattern, we mean the depth and breadth of dispersion.Factors that may affect dispersion patterns, include the type of tissuebeing treated, the volume of blood flow through the targeted tissue, thekinematics and viscosity of the injectate, the volume of and theinjection pressure of the injectate, and the distance between the targetsite and the dispersion orifice(s).

[0166] The pressure of the injectate is one of the most importantfactors. It will significantly affect the depth of penetration into atarget site. The depth of penetration may be crucial for certainapplications. For example, when using a side-shooting catheter-basedinjection device of the present invention in an intravascularapplication, a physician may want to limit penetration of the injectateto only the endothelial lining of the vessel. On the other hand, he maywant to penetrate through the adventitial layer of the vessel wall andinto the surrounding tissue bed. Accordingly, the proper injectionpressure should be carefully selected for the application at hand.

[0167] Different types of tissue (e.g., myocardial, vascular, cartilage,malignancies, etc) or substances (e.g., atherosclerotic plaque,thrombus, etc.) have physiological differences that may affect thedispersion characteristics of an injected solution. For example,muscular tissue such as the myocardium has what are known asinterstitial tissue planes, i.e., parallel planes of tissue defined byseams running between the planes. The point or line of contact between avessel and its adjacent tissue also define and interstitial tissueplane. These planes may affect the path of the injectate as it willfollow the path of least resistance and run along the seams rather thantransversely penetrating the tissue planes.

[0168] Exposure of the injected solution to a blood supply can alsoeffect dispersion and the intended medical outcome of the procedure. Forexample, in the case of infarcted myocardium, it is important for theinjected angiogenic growth factor to be exposed to at least some bloodsupply by which it is nourished in order proliferate. Additionally, dueto the individual cellular and chemical composition of each solution,each solution is likely to have a different kinematic response whiledispersing through tissue. The viscosity, cell size, valence bonding,and other chemical and biological characteristics of the solution mayalso affect its kinematic behavior.

[0169] For purposes of this description, the devices and methods of thepresent invention have been described primarily for use in cardiac andvascular applications, and more specifically for the treatment ofischemia, atherosclerosis and thrombosis; however, other applications ofthe present invention are contemplated. These include but are notlimited to the treatment of tumors, rheumatoid arthritis, chronicinflammatory diseases, genital-ureteral conditions and variousretinopathies. Also, although only specific examples of injectablesolutions were mentioned in the description, any suitable biologic,pharmaceuticals, biopharmaceuticals, or other agents which are notnecessarily categorized as a drug (e.g., alcohol) may be delivered andinjected by the devices and methods of the present invention.

[0170] Each of the various components of the solution delivery/injectionsystems of the present invention, the injection device, the solutionampule and the solution dispersion means, may be supplied integrallyassembled and packaged, or may be individually packaged, or otherwisepackaged in any combination of the components. The ampules may besupplied with a pre-filled, selected volume (one or more doses) ofsolution directly from the supplier, or may be filled by the user at thetime of the procedure and then refilled with additional doses, eitherwithin the same procedure, or in a later procedure. Additionally, any orall of the components may be reusable, or disposable, single-use (orprocedure) units.

[0171] For all embodiments of the present invention, the end effector ofthe dispersion means is designed for optimally delivering and dispersinga solution through the surface of the target organ or tissue orsubstance without using the end effector itself or another implement tofirst penetrate and create a working space within the tissue.

[0172] From the foregoing, it will be appreciated that althoughembodiments of the invention have been described herein for purposes ofillustration, various modifications may be made without deviating fromthe spirit of the invention. Thus, the present invention is not limitedto the embodiments described herein, but rather is defined by the,claims which follow.

What is claimed is:
 1. A system for injecting an agent into a targetsite within the body, comprising: an ampule having a reservoir forholding a volume of agent, the reservoir having at least one reservoirorifice; a dispersion means distal to the ampule and having at least onedispersion orifice; at least one pathway in fluid communication betweenthe at least one reservoir orifice and the at least one dispersionorifice; and a propulsion mechanism operatively coupled to the reservoirfor propelling the agent from within the reservoir, through the at leastone reservoir orifice, the at least one pathway, and the at least onedispersion orifice and into the target site at a pressure sufficient tocause the agent to penetrate the target site without penetrating thetarget site with the dispersion means; wherein: the dispersion meanscomprises a fixture having an atraumatic target-facing surface withinwhich the at least one dispersion orifice is located; and thetarget-facing surface is smooth and substantially planar.
 2. The systemof claim 1, wherein the fixture has a cylindrical cap configuration 3.The system of claim 1 wherein the target-facing surface has a circularshape.
 4. The system of claim 1 wherein the target-facing surface has anoval shape.
 5. The system of claim 1 wherein the target-facing surfacehas an elliptical shape.
 6. The system of claim 1 wherein thetarget-facing surface has an arched cone configuration having a vertexand an arched portion.
 7. The system of claim 1 wherein thetarget-facing surface has a single dispersion orifice.
 8. The system ofclaim 1 wherein the target-facing surface has a plurality of dispersionorifices in a quadrangle arrangement.
 9. The system of claim 1 whereinthe target-facing surface has a plurality of dispersion orificesarranged along the perimeter of the target-facing surface.
 10. Thesystem of claim 1 wherein the target-facing surface has a plurality ofdispersion orifices arranged in an annular array.
 11. The system ofclaim 6 wherein the target-facing surface has a plurality of dispersionorifices arranged along the perimeter of the arched portion.
 12. Thesystem of claim 7 having a single pathway in fluid communication betweenthe single reservoir orifice and the single dispersion orifice.
 13. Thesystem of claim 1 wherein the dispersion means has a profile sufficientto be delivered through a less invasive opening.
 14. The system of claim13 wherein the less invasive opening is a port positioned within thepatient's body.
 15. The system of claim 13 further comprising anendoscope integrally coupled with the system.
 16. The system of claim 8wherein the dispersion means comprises a cannula having a proximal endand a distal end having an atraumatic distal tip, and having a lumenextending there between.
 17. The system of claim 16 wherein theatraumatic distal tip comprises a target-facing surface.